Factor xa inhibitors

ABSTRACT

The present invention is directed to compounds represented by Formula (I) or a pharmaceutically acceptable salt, ester, or prodrug thereof which are inhibitors of Factor Xa. The present invention is also directed to and intermediates used in making such compounds, pharmaceutical compositions containing such compounds, methods to prevent or treat a number of conditions characterized by undesired thrombosis and methods of inhibiting the coagulation of a blood sample.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/158,274, filed Jun. 20, 2005, which claims thebenefit of U.S. Provisional Application No. 60/580,899, filed Jun. 18,2004, which applications are incorporated herein by reference in theirentireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to novel compounds which act as inhibitors ofFactor Xa. This invention is also directed to pharmaceuticalcompositions containing the compounds and methods of using the compoundsor compositions to treat a condition characterized by undesiredthrombosis. The invention is also directed to methods of making thecompounds described herein.

2. State of the Art

Hemostasis, the control of bleeding, occurs by surgical means, or by thephysiological properties of vasoconstriction and coagulation. Thisinvention is particularly concerned with blood coagulation and ways inwhich it assists in maintaining the integrity of mammalian circulationafter injury, inflammation, disease, congenital defect, dysfunction orother disruption. Although platelets and blood coagulation are bothinvolved in restoring hemostasis and in thrombotic diseases, certaincomponents of the coagulation cascade are primarily responsible for theamplification and acceleration of the processes involved in plateletaggregation and fibrin deposition which are major events in thrombosisand hemostasis.

Clot formation involves the conversion of fibrinogen to fibrin whichpolymerizes into a network to restore hemostasis after injury. A similarprocess results in occluded blood vessels in thrombotic diseases. Theconversion of fibrinogen to fibrin is catalyzed by thrombin, the endproduct of a series of reactions in the blood coagulation cascade.Thrombin is also a key player in activating platelets, therebycontributing to thrombosis under conditions of both arterial and venousblood flow. For these reasons, it has been postulated that efficientregulation of thrombin can lead to efficient regulation of thrombosis.Several classes of currently used anticoagulants directly or indirectlyaffect thrombin (i.e. unfractionated heparins, low-molecular weightheparins, heparin-like compounds, pentasaccharide and warfarin). Director indirect inhibition of thrombin activity has also been the focus of avariety of anticoagulants in clinical development (reviewed by Erikssonand Quinlan, Drugs 11: 1411-1429, 2006).

Prothrombin, the precursor for thrombin, is converted to the activeenzyme by factor Xa. Localized activation of tissue factor/factor VIIamediated factor Xa generation is amplified by the factor IXa/factorVIIIa complex and leads to prothrombinase assembly on activatedplatelets. Factor Xa, as a part of the prothrombinase complex, is thesole enzyme responsible for sustained thrombin formation in thevasculature. Factor Xa is a serine protease, the activated form of itsprecursor Factor X, and a member of the calcium ion binding, gammacarboxyglutamic acid (GLA)-containing, vitamin K dependent, bloodcoagulation factors. Unlike thrombin, which acts on a variety of proteinsubstrates including fibrinogen and the PAR receptors (Proteaseactivated receptors, Coughlin, J Thrombosis Haemostasis 3: 1800-1814,2005), factor Xa appears to have a single physiologic substrate, namelyprothrombin. Since one molecule of factor Xa may be able to generategreater than 1000 molecules of thrombin (Mann, et al., J. Thrombosis.Haemostasis 1: 1504-1514, 2003), direct inhibition of factor Xa as a wayof indirectly inhibiting the formation of thrombin is considered anefficient anticoagulant strategy. This assertion is based on the keyrole of prothrombinase in thrombin synthesis and on the fact thatinhibition of prothrombinase will have a pronounced effect on theoverall platelet aggregation and clotting pathways. Activated proteasessuch as factor VIIa, factor IXa or factor Xa have poor proteolyticactivity on their own. However, their assembly into cofactor-dependent,membrane-bound complexes significantly enhances their catalyticefficiencies. This effect is most dramatic for factor Xa, where theefficiency is increased by a factor of 10⁵ (Mann, et al., Blood76(1):1-16, 1990). Due to the higher concentration of the zymogenspresent in blood (1.4 micromolar prothrombin versus 150 nanomolar factorX) and the kinetics of activation, a smaller amount of factor Xa thanthrombin needs to be inhibited to achieve an anticoagulant effect.Indirect proof of the hypothesis of superiority of factor Xa as atherapeutic target compared to thrombin can also be found in clinicaltrials for the prevention of deep vein thrombosis. Fondaparinux, anantithrombin III dependent factor Xa inhibitor, was proven to besuperior to enoxaparin (a low molecular weight heparin that inhibitsboth thrombin and factor Xa) in four trials of orthopedic surgery(Turpie, et al., Archives Internal Medicine 162(16): 1833-1840, 2002).Therefore, it has been suggested that compounds which selectivelyinhibit factor Xa may be useful as in vitro diagnostic agents, or fortherapeutic administration in certain thrombotic disorders, see e.g., WO94/13693.

Several Factor Xa inhibitors have been reported as polypeptides derivedfrom hematophagous organisms, as well as compounds which are not largepolypeptide-type inhibitors. Additional Factor Xa inhibitors includesmall molecule organic compounds, such as nitrogen containingheterocyclic compounds which have amidino substituent groups, whereintwo functional groups of the compounds can bind to Factor Xa at two ofits active sites. For example, WO 98/28269 describes pyrazole compoundshaving a terminal C(═NH)—NH₂ group; WO 97/21437 describes benzimidazolecompounds substituted by a basic radical which are connected to anaphthyl group via a straight or branched chain alkylene, —C(═O) or—S(═O)₂ bridging group; WO 99/10316 describes compounds having a4-phenyl-N-alkylamidino-piperidine and4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenylgroup via a carboxamidealkyleneamino bridge; and EP 798295 describescompounds having a 4-phenoxy-N-alkylamidino-piperidine group connectedto an amidinonaphthyl group via a substituted or unsubstitutedsulfonamide or carboxamide bridging group. Additional reported Factor Xainhibitors include those having a structure comprising a phenyl-amidino,phenyl and halo-phenyl connected via amide linkages (U.S. Pat. No.6,844,367 B1). Other Factor Xa inhibitors by the same group havereplaced the halo-phenyl with a halo-pyridyl (see U.S. Pat. Nos.6,376,515 B2 and 6,835,739 B2).

There exists a need for effective therapeutic agents for the regulationof hemostasis, and for the prevention and treatment of thrombusformation and other pathological processes in the vasculature induced bythrombin such as restenosis and inflammation. In particular, therecontinues to be a need for compounds which selectively inhibit factor Xaor its precursors. Compounds that have different combinations ofbridging groups and functional groups than compounds previouslydiscovered are needed, particularly compounds which selectively orpreferentially bind to Factor Xa. Compounds with a higher degree ofbinding to Factor Xa than to thrombin are desired, especially thosecompounds having good bioavailability and/or solubility.

BRIEF SUMMARY OF THE INVENTION

The present invention provides in one aspect, compounds having theformula:

In formula (I), the symbol R¹ is halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, andC₂₋₈ alkynyl.

The symbol R² is hydrogen or C₁₋₄ alkyl.

The symbol A is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to ring B andthe dashed line indicates the point of attachment to the rest of themolecule;

The symbol R³ is independently hydrogen or R^(3a), wherein R^(3a) isindependently selected from the group consisting of halogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, and C₂₋₈ alkynyl.

The subscript m is 0, 1, 2, or 3.

The symbol X is C—R⁴ or N.

The symbol Y is C—R⁵ or N provided that X and Y are not both N.

In some embodiments, X and Y are C and are fused to form a 6-memberedaryl, heteroaryl, or heterocyclic ring.

The symbol R⁴ is selected from the group consisting of hydrogen,halogen, and

wherein R^(4a) is hydrogen or C₁₋₈ alkyl.

The symbol R⁵ is selected from the group consisting of hydrogen,halogen, and C_(hs) alkoxy.

The symbol R⁶ is selected from the group consisting of —R^(6a),—NR^(7a)R^(7b), —NR^(7a)C(O)R^(7c), —NR^(7a)C(O)OR^(7c),—CONR^(8a)R^(8b), —OR^(7c), —SR^(7c), —C(═NR^(7a))NR^(8a)R^(8b),—S(O)₂NR^(8a)R^(8b), and —S(O)₂R^(7c).

In some embodiments, R⁵ and R⁶ join together with the atoms boundthereto to form a 6-membered aryl, heteroaryl, or heterocyclic ringfused to ring B.

The symbol R^(6a) is selected from the group consisting of

wherein R⁸ can be at any position suitable for a substituent, and if R⁸is attached to a nitrogen atom, then it replaces the hydrogen atomattached thereto.

The symbol R^(7a) and R^(7b) are independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with oneto three R⁹.

The symbol R^(7c) is selected from the group consisting of aryl,heteroaryl, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with one to three R⁹.

The symbol R⁸ is independently selected from the group consisting ofnitro, hydroxy, —CO₂H, —C(O)R^(8c), —C(O)NR^(8a)R^(8b), —NR^(8a)R^(8b),—SO₂NR^(8a)R^(8b), halogen, C₁₋₈ alkyl, and C₁₋₈ alkoxy wherein saidC₁₋₈ alkyl and C₁₋₈ alkoxy are optionally substituted with one to threeR⁹.

The symbol R^(8a) and R^(8b) are independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with oneto three R⁹, or R^(8a) and R^(8b) join together along with the atombound thereto to form a 5 to 7 membered heterocyclic ring optionallysubstituted with one to three R⁹ and optionally having one additionalring heteroatom selected from N, O, or S.

The symbol R^(8C) is selected from the group consisting of C₁₋₈ alkyland C₁₋₈ alkyl substituted with one to three R⁹.

The symbol R⁹ is independently selected from the group consisting ofhalogen, heterocyclic, heteroaryl, —OH, —R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —SO₂NH₂, —C(O)NH₂, —C(O)R¹⁰, —C(NH)R¹⁰, —NHC(O)R¹⁰,—NHC(NH)R¹⁰, —NHC(O)NH₂, —CO₂H, —NH₂, —NHR¹⁰, —N(R¹⁰)₂, and —N(R¹⁰)₃.

The symbol R¹⁰ is independently C₁₋₆ alkyl.

The subscript n is 0, 1, 2, or 3.

Formula (I) is with the proviso that when X is C—R⁴, Y is C—R⁵, R⁶ isR^(6a), and A is

then R^(6a) is bound to ring B through a carbon atom.

The present invention also contemplates pharmaceutically acceptablesalts, esters, and prodrugs of formula (I).

The present invention further provides chemical intermediates,pharmaceutical compositions and methods for preventing or treating acondition in a mammal characterized by undesired thrombosis comprisingthe step of administering to said mammal a therapeutically effectiveamount of a compound of the present invention. Such conditions includebut are not limited to acute coronary syndrome, myocardial infarction,unstable angina, refractory angina, occlusive coronary thrombusoccurring post-thrombolytic therapy or post-coronary angioplasty, athrombotically mediated cerebrovascular syndrome, embolic stroke,thrombotic stroke, transient ischemic attacks, venous thrombosis, deepvenous thrombosis, pulmonary embolus, coagulopathy, disseminatedintravascular coagulation, thrombotic thrombocytopenic purpura,thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation such as cardiac or other intravascularcatheterization, intra-aortic balloon pump, coronary stent or cardiacvalve, conditions requiring the fitting of prosthetic devices, and thelike.

The present invention further provides methods for inhibiting thecoagulation of a blood sample comprising contacting said sample with acompound of the present invention.

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group is one having one or more, preferably 1 to 3,double bonds. Similarly, the term “alkynyl” refers to an unsaturatedalkyl group having one or more, preferably 1 to 3, triple bonds.Examples of such unsaturated alkyl groups include vinyl, 2-propenyl,crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆ cycloalkyl) and being fully saturatedbetween ring vertices. The term “cycloalkenyl” refers to a cycloalkylgroup that has at least one point of alkenyl unsaturation between thering vertices. The term “cycloalkynyl” refers to a cycloalkyl group thathas at least one point of alkynyl unsaturation between the ringvertices. When “cycloalkyl” is used in combination with “alkyl”, as inC₃₋₅ cycloalkyl-alkyl, the cycloalkyl portion is meant to have thestated number of carbon atoms (e.g., from three to five carbon atoms),while the alkyl portion is an alkylene moiety having from one to threecarbon atoms (e.g., —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—).

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms.

The terms “alkoxy,” “alkylamino,” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom (—O-alkyl),an amino group, or a sulfur atom (—S-alkyl), respectively. Additionally,for dialkylamino groups (typically provided as —NR^(a)R^(b) or a variantthereof, where R^(a) and R^(b) are independently alkyl or substitutedalkyl), the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl up to the maximumnumber of halogens permitted. For example, the term “C₁₋₄ haloalkyl” ismean to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “hydroxy” or “hydroxyl” refers to the group —OH.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon group containing from 6 to 14 carbon atoms, whichcan be a single ring or multiple rings (up to three rings) which arefused together or linked covalently. The term “heteroaryl” refers toaryl groups (or rings) that contain from one to five heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom or through a carbon atom and can contain 5to 10 carbon atoms. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl, while non-limiting examples of heteroaryl groupsinclude 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl,5-benzothiazolyl, purinyl, 2-benzimidazolyl, benzopyrazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. If not specifically stated, substituents foreach of the above noted aryl and heteroaryl ring systems are selectedfrom the group of acceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl or heteroaryl group is attached to analkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like).

The term “heterocycle” or “heterocyclyl” or “heterocyclic” refers to asaturated or unsaturated non-aromatic cyclic group containing at leastone sulfur, nitrogen or oxygen heteroatom. Each heterocycle can beattached at any available ring carbon or heteroatom. Each heterocyclemay have one or more rings. When multiple rings are present, they can befused together or linked covalently. Each heterocycle must contain atleast one heteroatom (typically 1 to 5 heteroatoms) selected fromnitrogen, oxygen or sulfur. Preferably, these groups contain 1-10 carbonatoms, 0-5 nitrogen atoms, 0-2 sulfur atoms and 0-2 oxygen atoms,wherein the nitrogen and sulfur atoms are optionally oxidized, and thenitrogen atom(s) are optionally quaternized. More preferably, thesegroups contain 0-3 nitrogen atoms, 0-1 sulfur atoms and 0-1 oxygenatoms.

Non-limiting examples of heterocycle and heteroaryl groups includepyridine, pyridimidine, pyrazine, morpholin-3-one, piperazine-2-one,pyridine-2-one, piperidine, morpholine, piperazine, isoxazole,isothiazole, pyrazole, imidazole, oxazole, thiazole, isoxazoline,pyrazoline, imidazoline, 1,2,3-triazole, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole,1,2,4-thiadiazole, pyrazol-5-one, pyrrolidine-2,5-dione,imidazolidine-2,4-dione, pyrrolidine, pyrrole, furan, thiophene, and thelike.

The term “heterocycloalkyl” refers to the group alkylene-heterocycle,wherein both heterocycle and alkylene are as defined above.

The above terms (e.g., “aryl” and “heteroaryl”), in some embodiments,will include both substituted and unsubstituted forms of the indicatedradical. Preferred substituents for each type of radical are providedbelow. For brevity, the terms aryl and heteroaryl will refer tosubstituted or unsubstituted versions as provided below.

Substituents for the aryl and heteroaryl groups are varied and aregenerally selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′,—CN, —NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′,—NR″C(O)₂R′, —NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH,—NH—C(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR′S(O)₂R″, —N₃,perfluoro(C₁-C₄)alkoxy, and perfluoro(C₁-C₄)alkyl, in a number rangingfrom zero to the total number of open valences on the aromatic ringsystem; and where R′, R″ and R′″ are independently selected fromhydrogen, C₁₋₈alkyl, C₃₋₆cycloalkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C₁₋₄alkyl, andunsubstituted aryloxy-C₁₋₄alkyl. Other suitable substituents includeeach of the above aryl substituents attached to a ring atom by analkylene tether of from 1-4 carbon atoms.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)-U-, wherein T and U are independently —NH—, —O—, —CH₂—or a single bond, and q is an integer of from 0 to 2.

Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)-B-, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t), where s and t are independently integers of from0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—. Thesubstituent R′ in —NR'- and —S(O)₂NR′— is selected from hydrogen orunsubstituted C₁₋₆alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, e.g., Berge, S.M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science,1977, 66, 1-19). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

Accordingly, in one embodiment provided is a compound having Formula (I)or a pharmaceutically acceptable salt, ester, or prodrug thereof:

In Formula (I), the symbol R¹ is halogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, andC₂₋₈ alkynyl.

The symbol R² is hydrogen or C₁₋₄ alkyl.

The symbol A is selected from the group consisting of:

wherein the wavy line indicates the point of attachment to ring B andthe dashed line indicates the point of attachment to the rest of themolecule.

The symbol R³ is independently hydrogen or R^(3a), wherein R^(3a) isindependently selected from the group consisting of halogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, and C₂₋₈ alkynyl.

The subscript m is 0, 1, 2, or 3.

The symbol X is C—R⁴ or N.

The symbol Y is C—R⁵ or N provided that X and Y are not both N. In someembodiments, X and Y are C and are fused to form a 6-membered aryl,heteroaryl, or heterocyclic ring.

The symbol R⁴ is selected from the group consisting of hydrogen,halogen, and

wherein R^(4a) is hydrogen or C₁₋₈ alkyl.

The symbol R⁵ is selected from the group consisting of hydrogen,halogen, and C₁₋₈ alkoxy; or R⁵ and R⁶ join together along with the atombound thereto to form a 6-membered aryl, heteroaryl, or heterocyclicring fused to ring B.

The symbol R⁶ is selected from the group consisting of —R^(6a),—NR^(7a)R^(7b), —NR^(7a)C(O)R^(7c), —NR^(7a)C(O)OR^(7c),—CONR^(8a)R^(8b), —OR^(7c), —SR^(7c), —C(═NR^(7a))NR^(8a)R^(8b),—S(O)₂NR^(8a)R^(8b), and —S(O)₂R^(7c).

The symbol R^(6a) is selected from the group consisting of

wherein R⁸ an be at any position suitable for a substituent, and if R⁸is attached to a nitrogen atom, then it replaces the hydrogen atomattached thereto.

The symbol R^(7a) and R^(7b) are independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with oneto three R⁹.

The symbol R^(7c) is selected from the group consisting of aryl,heteroaryl, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with one to three R⁹.

The symbol R⁸ is independently selected from the group consisting ofnitro, hydroxy, —CO₂H, —C(O)R^(8c), —C(O)NR^(8a)R^(8b), —NR^(8a)R^(8b),—SO₂NR^(8a)R^(8b), halogen, C₁₋₈ alkyl, and C₁₋₈ alkoxy wherein saidC₁₋₈ alkyl and C₁₋₈ alkoxy are optionally substituted with one to threeR⁹.

The symbol R^(8a) and R^(8b) are independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with oneto three R⁹, or R^(8a) and R^(8b) together form a 5 to 7 memberedheterocyclic ring optionally substituted with one to three R⁹ andoptionally having one additional ring heteroatom selected from N, O, orS.

The symbol R^(8c) is selected from the group consisting of C₁₋₈ alkyland C₁₋₈ alkyl substituted with one to three R⁹.

The symbol R⁹ is independently selected from the group consisting ofhalogen, heterocyclic, heteroaryl, —OH, —R¹⁰, —OR¹⁰, —S(O)R¹⁰,—S(O)₂R¹⁰, —SO₂NH₂, —C(O)NH₂, —C(O)R¹⁰, —C(NH)R¹⁰, —NHC(O)R¹⁰,—NHC(NH)R¹⁰, —NHC(O)NH₂, —CO₂H, —NH₂, —NHR¹⁰, —N(R¹⁰)₂, and —N(R¹⁰)₃ ⁺.

The symbol R¹⁰ is independently C₁₋₆ alkyl.

The subscript n is 0, 1, 2, or 3.

Formula (I) is with the proviso that when X is C—R⁴, Y is C—R⁵, R⁶ isR^(6a), and A is

then R^(6a) is bound to ring B through a carbon atom.

With respect to the above formula, there are a number of specificembodiments of the invention. In one group of embodiments, R¹ is2-chloro.

In another group of embodiments, R² is hydrogen.

In another group of embodiments, X and Y are both CH.

In another group of embodiments, A is selected from the group consistingof:

In another group of embodiments, R⁶ is R^(6a).

In another group of embodiments, R^(6a) is selected from the groupconsisting of:

In another group of embodiments, R⁶ is selected from the groupconsisting of:

In another group of embodiments, R⁶ is selected from the groupconsisting of:

In another group of embodiments, R⁶ is selected from the groupconsisting of:

In another group of embodiments, R⁶ is selected from the groupconsisting of:

In another group of embodiments, R⁶ is selected from the groupconsisting of:

In another group of embodiments, R⁶ is

and R⁸ is as previously defined. In still another group of embodiments,R⁸ is selected from the group consisting of hydrogen,

In another embodiment, ring B is

In another embodiment, the compound is a compound selected from Table 1or a pharmaceutically acceptable salt, ester, or prodrug thereof.

TABLE 1 Compound Structure Name 1

5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 2

5-Chloro-N-((1-(2-(4-ethylpiperazin- 1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 3

5-Chloro-N-((1-(2-(4- isopropylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 4

5-Chloro-N-((1-(4-(2-oxopyrimidin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 5

5-Chloro-N-((1-(4-(1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 6

5-Chloro-N-((1-(4-(2,4- dimethoxypyrimidin-5-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 7

5-Chloro-N-((1-(4-(2- ((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 8

5-Chloro-N-((1-(4-(2-methyl-1H- imidazol-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 9

5-Chloro-N-((1-(4-(4-methyl-1,4- diazepan-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 10

5-Chloro-N-((1-(4-(2- oxoimidazolidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 11

5-Chloro-N-((1-(2′-methoxybiphenyl- 4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 12

5-Chloro-N-((1-(2′-hydroxybiphenyl- 4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 13

5-Chloro-N-((1-(2′- (trifluoromethoxy)biphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 14

5-Chloro-N-((1-(4-(6-chloropyridin- 3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 15

N-((1-(4-(1H-Indol-2-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide 16

5-Chloro-N-((1-(4- (methylsulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 17

5-Chloro-N-((1-(3-fluoro-2′- sulfamoylbiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 18

5-Chloro-N-((1-(4-(pyrrolidine-1- carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 19

5-Chloro-N-((1-(4-(2,5-dihydro-1H- pyrrole-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 20

N-((1-(4-Carbamoylphenyl)- 1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide 21

N-((1-(4-(2-Amino-N- methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide 22

5-Chloro-N-((1-(4-(methyl(2- (methylamino)ethyl)amino)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 23

5-Chloro-N-((1-(4- (methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 24

5-Chloro-N-((1-(4-(N- methylpropionamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 25

Ethyl 4-(4-((5-chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl(methyl)carbamate 26

5-Chloro-N-((1-(4-(2-methoxy-N- methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 27

5-Chloro-N-((1-(4-(2- (dimethylamino)-N-methylacetamido)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene-2-carboxamide 28

5-Chloro-N-((1-(4-(N- methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 29

5-Chloro-N-((1-(4-(2- hydroxyethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 30

5-Chloro-N-((1-(4-(6-oxo-1,6- dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 31

5-Chloro-N-((3-(2-fluoro-4-(2- oxopyridin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazol-5- yl)methyl)thiophene-2-carboxamide 32

5-Chloro-N-((5-oxo-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-4,5-dihydro-1H-pyrazol-3- yl)methyl)thiophene-2-carboxamide 33

5-Chloro-N-((2-oxo-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1,2-dihydropyridin-3- yl)methyl)thiophene-2-carboxamide 34

5-Chloro-N-((6-oxo-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1,6-dihydropyridin-3- yl)methyl)thiophene-2-carboxamide 35

5-Chloro-N-((1-methyl-2-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 36

5-Chloro-N-((1-(4-iodophenyl)-1H- imidazol-4-yl)methyl)thiophene-2-carboxamide 37

5-Chloro-N-((1-(4-(1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene- 2-carboxamide 38

5-Chloro-N-((1-(4-(2- methoxypyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 39

5-Chloro-N-((1-(4-(2-oxo-1,2- dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 40

5-Chloro-N-((1-(4-(1-methyl-2-oxo- 1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 41

N-((1-(4-Aminophenyl)-1H-imidazol- 4-yl)methyl)-5-chlorothiophene-2-carboxamide 42

5-Chloro-N-((1-(4-(2,5-dihydro-1H- pyrrole-1-carbonyl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 43

4-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)benzamide 44

N-((1-(4-(2-Oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-4-yl)methyl)acetamide 45

5-Chloro-N-((1-(5-(2-oxopyridin- 1(2H)-yl)pyridin-2-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 46

5-Chloro-N-((1-(6-(2-oxopyridin- 1(2H)-yl)pyridin-3-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 47

5-Ch1oro-N-((2,5-dibromo-1-(4-(N,N- dimethylcarbamimidoyl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2- carboxamide 48

5-Chloro-N-((2,5-dibromo-1-(4- (imino(pyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2-carboxamide 49

5-Chloro-N-((2,5-dibromo-1-(4-(1- methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene-2-carboxamide 50

5-Chloro-N-((1-(4-(9-methyl-2,6- dioxo-1H-purin-3(2H,6H,9H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 51

5-Chloro-N-((1-(4-(1-methyl-6-oxo- 1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-5-yl)methyl)thiophene- 2-carboxamide 52

5-Chloro-N-((4-methyl-1-(4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-5-yl)methyl)thiophene-2- carboxamide 53

5-Chloro-N-((1-(4-(2-oxopyrazin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 54

5-Chloro-N-((1-(2-fluoro-4-(2- oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 55

5-Chloro-N-((1-(2-fluoro-4-(2- oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 56

5-Chloro-N-((1-(4-(2- oxotetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 57

5-Chloro-N-((1-(2-fluoro-4-(2-oxo- tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 58

5-Chloro-N-((1-(2-fluoro-4-(3- methyl-2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide59

5-Chloro-N-((1-(2-fluoro-4-(2- oxopiperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 60

5-Chloro-N-((1-(3-fluoro-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 61

5-Chloro-N-((1-(4-(3-hydroxy-2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 62

5-Chloro-N-((1-(4-(3-(2- hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 63

5-Chloro-N-((1-(4-(3-(2- methoxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 64

5-Chloro-N-((1-(4-(3-(2- (dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 65

5-Chloro-N-((1-(4-(3-(2- (dimethyl(dimethylamino)amino)ethoxy)-2-oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 66

5-Chloro-N-((1-(4-(2-oxo-3-(2- (piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 67

5-Chloro-N-((1-(4-(2-oxo-3-(3- (piperidin-1-yl)propoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide68

5-Chloro-N-((1-(4-(3-(2- (methylthio)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide69

5-Chloro-N-((1-(4-(3-(2- (methylsulfinyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 70

5-Chloro-N-((1-(4-(3-(2- (methylsulfonyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 71

5-Chloro-N-((1-(4-(3-(2- morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide72

N-((1-(4-(3-(2-(1H-Imidazol-1- yl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)-5-chlorothiophene-2-carboxamide 73

5-Chloro-N-((1-(4-(3-((1-methyl-1H- imidazol-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 74

5-Chloro-N-((1-(4-(5-hydroxy-2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 75

5-Chloro-N-((1-(4-(5-(2- (dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 76

5-Chloro-N-((1-(4-(2-oxo-5-(2- (piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 77

5-Chloro-N-((1-(4-(5-(2- morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide78

5-Chloro-N-((1-(4-(5-nitro-2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 79

N-((1-(4-(4-Amino-2-oxopyrimidin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2- carboxamide 80

5-Chloro-N-((1-(4-(2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 81

N-((1-(4-(4-Amino-5-fluoro-2- oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5- chlorothiophene-2-carboxamide 82

5-Chloro-N-((1-(4-(3-methyl-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 83

5-Chloro-N-((1-(4-(2-oxopiperazin-1- yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 84

5-Chloro-N-((1-(4-(4-methyl-2- oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 85

5-Chloro-N-((1-(4-(4-isopropyl-2- oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide 86

4-(4-(4-((5-Chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-oxopiperazine- 1-carboxamide 87

5-Chloro-N-((1-(4-(3-hydroxy-2- oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 88

5-Chloro-N-((1-(4-(4-(2- (dimethylamino)ethyl)-2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 89

5-Chloro-N-((1-(4-(3-hydroxy-6- oxopyridazin-1(6H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 90

1-(4-(2-Oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3-triazol-4-yl)methylcarbamoyl)benzoic acid 91

N-((1-(2-(3-Oxopiperazin-1-yl)-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 92

5-Chloro-N-((1-(4-(1-methyl-4,5- dihydro-1H-imidazol-2-yl)phenyl)-1H-1,2,3-triazol-5- yl)methyl)thiophene-2-carboxamide 93

5-Chloro-N-((1-(4-(N,N- dimethylcarbamimidoyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene- 2-carboxamide 94

5-Chloro-N-((1-(4-(imino(pyrrolidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide 95

5-Chloro-N-((1-(4-(imino(piperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide 96

N-((1-(4-Carbamoylphenyl)-1H- 1,2,3-triazol-5-yl)methyl)-5-chlorothiophene-2-carboxamide 97

5-Chloro-N-((1-(4- (methylsulfonyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2- carboxamide 98

5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide 99

5-Chloro-N-((1-(4-(pyridin-2- ylthio)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide 100

5-Chloro-N-((1-(6-(pyrrolidin-1- yl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 101

1-(5-(4-((5-Chlorothiophene-2- carboxamido)methyl)-1H-1,2,3-triazol-1-yl)pyridin-2-yl)piperidine-4- carboxylic acid 102

N-((1-(6-(Azepan-1-yl)pyridin-3-yl)- 1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide 103

5-Chloro-N-((1-(6-(4-methyl-1,4- diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2- carboxamide 104

N-((1-(6-(1,4-Diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)-5- chlorothiophene-2-carboxamide 105

5-Chloro-N-((1-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5- yl)methyl)thiophene-2-carboxamide 106

5-Chloro-N-((1-(6-(piperazin-1- yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide 107

5-Chloro-N-(4-(4-((5- chlorothiophene-2-carboxamido)methyl)-1H-imidazol-1- yl)benzyl)thiophene-2-carboxamide 108

5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide 109

5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide 110

5-Chloro-N-((1-(4-(4-methyl-1,4- diazepan-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide 111

5-Chloro-N-((1-(4-(2-oxopyrazin- 1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide 112

5-Chloro-N-((1-(4-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide 113

5-Chloro-N-((1-(3-(2-oxopyridin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide 114

5-Chloro-N-((1-(4-methyl-3-oxo-3,4- dihydro-2H-benzo[β][1,4]oxazin-7-yl)-1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 115

5-Chloro-N-((1-(3-methoxy-4-(2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 116

5-Chloro-N-((1-(5-(2-oxopyridin- 1(2H)-yl)quinolin-8-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2- carboxamide

All the preferred, more preferred, and most preferred compounds listedabove are selective inhibitors of Factor Xa.

Compositions

The present invention further provides compositions comprising one ormore compounds of Formula (I) or a pharmaceutically acceptable salt,ester, or prodrug thereof and a pharmaceutically acceptable excipient orcarrier. It will be appreciated that the compounds of Formula (I) inthis invention may be derivatized at functional groups to provideprodrug derivatives which are capable of conversion back to the parentcompounds in vivo. Examples of such prodrugs include the physiologicallyacceptable and metabolically labile ester derivatives, such asmethoxymethyl esters, methylthiomethyl esters, or pivaloyloxymethylesters derived from a hydroxyl group of the compound or a carbamoylmoiety derived from an amino group of the compound. Additionally, anyphysiologically acceptable equivalents of the compounds of Formula (I),similar to metabolically labile esters or carbamates, which are capableof producing the parent compounds of Formula (I) in vivo, are within thescope of this invention.

If pharmaceutically acceptable salts of the compounds of this inventionare utilized in these compositions, those salts are preferably derivedfrom inorganic or organic acids and bases. Included among such acidsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate,camphor sulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.Base salts include ammonium salts, alkali metal salts, such as sodiumand potassium salts, alkaline earth metal salts, such as calcium andmagnesium salts, salts with organic bases, such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth.

Furthermore, the basic nitrogen-containing groups may be quaternizedwith agents like lower alkyl halides, such as methyl, ethyl, propyl andbutyl chlorides, bromides and iodides; dialkyl sulfates, such asdimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides, suchas decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides;aralkyl halides, such as benzyl and phenethyl bromides and others. Wateror oil-soluble or dispersible products are thereby obtained.

The compounds utilized in the compositions and methods of this inventionmay also be modified by appending appropriate functionalities to enhanceselective biological properties. Such modifications are known in the artand include those which increase biological penetration into a givenbiological system (e.g., blood, lymphatic system, central nervoussystem, etc.), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a sterile liquid, such as oil, water, alcohol, andcombinations thereof. Pharmaceutically suitable surfactants, suspendingagents or emulsifying agents, may be added for oral or parenteraladministration. Suspensions may include oils, such as peanut oil, sesameoil, cottonseed oil, corn oil and olive oil. Suspension preparation mayalso contain esters of fatty acids, such as ethyl oleate, isopropylmyristate, fatty acid glycerides and acetylated fatty acid glycerides.Suspension formulations may include alcohols, such as ethanol, isopropylalcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, suchas poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil andpetrolatum, and water may also be used in suspension formulations.

Pharmaceutically acceptable excipients or carriers that may be used inthese compositions include ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffersubstances, such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylen e-block polymers, polyethylene glycol and wool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the invention may beadministered orally, parenterally, by inhalation spray, topically,rectally, nasally, buccally, vaginally or via an implanted reservoir.The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intra-articular, intra-synovial, intrasternal,intrathecal, intrahepatic, intralesional and intracranial injection orinfusion techniques. Preferably, the compositions are administeredorally or intravenously. The formulations of the invention may bedesigned as short-acting, fast-releasing, or long-acting. Still further,compounds can be administered in a local rather than systemic means,such as administration (e.g., injection) as a sustained releaseformulation.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol.

Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil may beemployed including synthetic mono- or di-glycerides. Fatty acids, suchas oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be in any orallyacceptable dosage form, including capsules, tablets, aqueous suspensionsor solutions. In the case of tablets for oral use, excipients orcarriers that are commonly used include lactose and corn starch.Lubricating agents, such as magnesium stearate, are also typicallyadded. For a capsule form, useful diluents include lactose and driedcornstarch. When aqueous suspensions are required for oral use, theactive ingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening, flavoring or coloring agents may also beadded.

Alternatively, the pharmaceutical compositions of this invention may bein the form of suppositories for rectal administration. These may beprepared by mixing the agent with a suitable non-irritating excipientwhich is solid at room temperature but liquid at rectal temperature andtherefore will melt in the rectum to release the drug. Such materialsinclude cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also be in atopical form, especially when the target of treatment includes areas ororgans readily accessible by topical application, including diseases ofthe eye, the skin, or the lower intestinal tract. Suitable topicalformulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include mineral oil, sorbitan monostearate, polysorbate 60,cetyl esters, wax, cetyl alcohol, 2-octyldodecanol, benzyl alcohol andwater.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative, such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment, such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons and/or other conventional solubilizing ordispersing agents.

Any of the above dosage forms containing effective amounts are withinthe bounds of routine experimentation and within the scope of theinvention. A therapeutically effective dose may vary depending upon theroute of administration and dosage form. The preferred compound orcompounds of the invention is a formulation that exhibits a hightherapeutic index. The therapeutic index is the dose ratio between toxicand therapeutic effects which can be expressed as the ratio between LD₅₀and ED₅₀. The LD₅₀ is the dose lethal to 50% of the population and theED₅₀ is the dose therapeutically effective in 50% of the population. TheLD₅₀ and ED₅₀ are determined by standard pharmaceutical procedures inanimal cell cultures or experimental animals.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers and dosage forms aregenerally known to those skilled in the art and are included in theinvention. It should be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex and diet of the patient, and thetime of administration, rate of excretion, drug combination, judgment ofthe treating physician and severity of the particular disease beingtreated. The amount of active ingredient(s) will also depend upon theparticular compound and other therapeutic agent, if present, in thecomposition.

Methods of Use

The invention provides methods of inhibiting or decreasing Factor Xaactivity as well as treating or ameliorating a Factor Xa associatedstate, symptom, disorder or disease in a patient in need thereof (e.g.,human or non-human). “Treating” within the context of the inventionmeans an alleviation of symptoms associated with a disorder or disease,or halt of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder.

The term “mammal” includes organisms which express Factor Xa. Examplesof mammals include mice, rats, cows, sheep, pigs, goats, horses, bears,monkeys, dogs, cats and, preferably, humans. Transgenic organisms whichexpress Factor Xa are also included in this definition.

The inventive methods comprise administering an effective amount of acompound or composition described herein to a mammal or non-humananimal. As used herein, “effective amount” of a compound or compositionof the invention includes those amounts that antagonize or inhibitFactor Xa. An amount which antagonizes or inhibits Factor Xa isdetectable, for example, by any assay capable of determining Factor Xaactivity, including the one described below as an illustrative testingmethod. Effective amounts may also include those amounts which alleviatesymptoms of a Factor Xa associated disorder treatable by inhibitingFactor Xa. Accordingly, “antagonists of Factor Xa” include compoundswhich interact with the Factor Xa and modulate, e.g., inhibit ordecrease, the ability of a second compound, e.g., another Factor Xaligand, to interact with the Factor Xa. The Factor Xa binding compoundsare preferably antagonists of Factor Xa. The language “Factor Xa bindingcompound” (e.g., exhibits binding affinity to the receptor) includesthose compounds which interact with Factor Xa resulting in modulation ofthe activity of Factor Xa. Factor Xa binding compounds may be identifiedusing an in vitro (e.g., cell and non-cell based) or in vivo method. Adescription of an in vitro method is provided below.

The amount of compound present in the methods and compositions describedherein should be sufficient to cause a detectable decrease in theseverity of the disorder, as measured by any of the assays described inthe examples. The amount of Factor Xa modulator needed will depend onthe effectiveness of the modulator for the given cell type and thelength of time required to treat the disorder. In certain embodiments,the compositions of this invention may further comprise anothertherapeutic agent. When a second agent is used, the second agent may beadministered either as a separate dosage form or as part of a singledosage form with the compounds or compositions of this invention. Whileone or more of the inventive compounds can be used in an application ofmonotherapy to treat a disorder, disease or symptom, they also may beused in combination therapy, in which the use of an inventive compoundor composition (therapeutic agent) is combined with the use of one ormore other therapeutic agents for treating the same and/or other typesof disorders, symptoms and diseases. Combination therapy includesadministration of the two or more therapeutic agents concurrently orsequentially. The agents may be administered in any order.Alternatively, the multiple therapeutic agents can be combined into asingle composition that can be administered to the patient. Forinstance, a single pharmaceutical composition could comprise thecompound or pharmaceutically acceptable salt or solvate according to theformula I, another therapeutic agent (e.g., methotrexate) or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable excipient or carrier.

The invention comprises a compound having the formula I, a method formaking an inventive compound, a method for making a pharmaceuticalcomposition from at least one inventive compound and at least onepharmaceutically acceptable carrier or excipient, and a method of usingone or more inventive compounds to treat a variety of disorders,symptoms and diseases (e.g., inflammatory, autoimmune, neurological,neurodegenerative, oncology and cardiovascular), such as RA,osteoarthritis, irritable bowel disease IBD, asthma, chronic obstructivepulmonary disease COPD and MS. The inventive compounds and theirpharmaceutically acceptable salts and/or neutral compositions may beformulated together with a pharmaceutically acceptable excipient orcarrier and the resulting composition may be administered in vivo tomammals, such as men, women and animals, to treat a variety ofdisorders, symptoms and diseases. Furthermore, the inventive compoundscan be used to prepare a medicament that is useful for treating avariety of disorders, symptoms and diseases.

Kits

Still another aspect of this invention is to provide a kit comprisingseparate containers in a single package, wherein the inventivepharmaceutical compounds, compositions and/or salts thereof are used incombination with pharmaceutically acceptable carriers to treat states,disorders, symptoms and diseases where Factor Xa plays a role.

General Methods

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York,1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2005, Volumes 1-65. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C. to about 75° C.

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates may be characterized by highperformance liquid chromatography (HPLC) using a Waters Alliancechromatography system with a 2695 Separation Module (Milford, Mass.).The analytical columns may be C-18 SpeedROD RP-18E Columns from MerckKGaA (Darmstadt, Germany). Alternately, characterization may beperformed using a Waters Unity (HPLC) system with Waters Acquity HPLCBEH C-18 2.1 mm×15 mm columns. A gradient elution may be used, typicallystarting with 5% acetonitrile/95% water and progressing to 95%acetonitrile over a period of 5 minutes for the Alliance system and 1minute for the Acquity system. All solvents may contain 0.1%trifluoroacetic acid (TFA). Compounds may be detected by ultravioletlight (UV) absorption at either 220 or 254 nm. HPLC solvents may be fromEMD Chemicals, Inc. (Gibbstown, N.J.). In some instances, purity may beassessed by thin layer chromatography (TLC) using glass backed silicagel plates, such as, for example, EMD Silica Gel 60 2.5 cm×7.5 cmplates. TLC results may be readily detected visually under ultravioletlight, or by employing well known iodine vapor and other variousstaining techniques.

Mass spectrometric analysis may be performed on one of two Agilent 1100series LCMS instruments with acetonitrile/water as the mobile phase. Onesystem using TFA as the modifier and measures in positive ion mode(reported as MH+, (M+1) or (M+H)+) and the other may use either formicacid or ammonium acetate and measures in both positive (reported as MH⁺,(M+1) or (M+H)⁺) and negative (reported as M−, (M−1) or (M−H)⁻) ionmodes.

Nuclear magnetic resonance (NMR) analysis may be performed on some ofthe compounds with a Varian 400 MHz NMR (Palo Alto, Calif.). Thespectral reference may be either TMS or the known chemical shift of thesolvent.

The purity of some of compounds of the invention may be assessed byelemental analysis (Robertson Microlit, Madison N.J.).

Melting points may be determined on a Laboratory Devices MeI-Tempapparatus (Holliston, Mass.).

Preparative separations may be carried out using either an Sq16x or anSg100c chromatography system and prepackaged silica gel columns allpurchased from Teledyne Isco, (Lincoln, Nebr.). Alternately, compoundsand intermediates may be purified by flash column chromatography usingsilica gel (230-400 mesh) packing material, or by HPLC using a C-18reversed phase column. Typical solvents employed for the Isco systemsand flash column chromatography may be dichloromethane, methanol, ethylacetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.Typical solvents employed for the reverse phase HPLC may be varyingconcentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

EXAMPLES

The following abbreviations are used throughout the Examples:

-   -   μL=microliter    -   μM=micromolar    -   AIBN=azobisisobutyronitrile    -   aq.=aqueous    -   Boc=tert-butoxycarbonyl    -   BOP=benzotriazol-1-yloxytris(dimethylamino)-phosphonium        hexafluorophosphate    -   conc.=concentrated    -   DBU=1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCM=dichloromethane    -   DIEA=diisopropylethyl amine    -   DMF=dimethyl formamide    -   DMSO=dimethyl sulfoxide    -   eq.=equivalent    -   EtOAc=ethyl acetate    -   g=gram    -   h or hr(s)=hour(s)    -   HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium        hexafluorophosphate    -   HOBt=N-hydroxybenzotriazole    -   HPLC=high pressure liquid chromatography    -   IC₅₀=the concentration of an inhibitor that is required for 50%        inhibition of an enzyme in vitro    -   kg=kilogram    -   M=molar    -   m/z=mass to charge ratio    -   MeOH=methanol    -   mg=milligram    -   MHz=mega Hertz    -   min=minute    -   mL=milliliter    -   mM=millimolar    -   mm=millimeter    -   mmol=millimole    -   mOD/min=millioptical density units per minute    -   MS=Mass Spec    -   N=Normal    -   NaSMc=sodium methylthiolate    -   NBS=N-bromosuccinamide    -   nBuOH=n-butanol    -   ng=nanogram    -   nM=nanomolar    -   nm=nanometer    -   Pd(PPh₃)₄=tetrakis-(triphenylphosphine)-palladium    -   PEG=polyethylene glycol    -   pM=picomolar    -   PPh₃ or Ph₃P=triphenyl phosphine    -   PyBOP=(benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   prep=preparative    -   Ra—Ni=Rainey Nickel    -   RT=room temperature    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   TMSCl=trimethylsilyl chloride    -   TLC=thin layer chromatography

Example 15-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(1)

Step 1:

2-Fluoro-4-iodoaniline (1.1, 6.50 g, 27.4 mmol) was dissolved in 25 mLTFA and stirred in ice bath. Solid NaNO₂ (2.07 g, 30.1 mmol) was addedin small portions. The resulting mixture was stirred for 30 min in icebath. Sodium azide (1.87 g, 28.8 mmol) was dissolved in 10 mL water andchilled in ice bath. This cold solution was then added to the TFAsolution in three portions. The mixture was stirred in ice bath for 1 hrand concentrated in vacuo to remove TFA. The residue was taken into 600mL DCM and washed with water three times. The organic phase was driedusing MgSO₄ and concentrated in vacuo to afford1-azido-2-fluoro-4-iodobenzene 1.2 as a brownish waxy solid in >99%yield. In the mean time, 5-chlorothiophene-2-carboxylic acid (1.3, 9.13g, 56 mmol) was dissolved in 200 mL dry DCM along with 0.5 mL dry DMF.To the vigorously stirred solution was carefully added oxalyl chlororide(14.7 mL, 169 mmol) dropwise. The resulting solution was stirred for 3hrs at RT and concentrated in vacuo. The residue was pumped to drynessand then dissolved in 300 mL dry DCM. To this solution was addedpropargylamine (5.8 mL, 84 mmol) dropwise. The mixture was stirred at RTovernight during which time solid precipitated out. 600 mL hexane wasadded and the mixture was vigorously stirred for a few hours. The solidwas collected by filtration and washed with hexane to give5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide 1.4 (9.47 g, 85%) whichwas used directly without further purification. MS found for C₈H₆ClNOSas (M+H)+ 200.0, 202.0 (chlorine pattern).

Step 2:

To a solution of the aryl azide 1.2 (27 mmol) and alkyne 1.4 (5.37 g, 27mmol) in 500 mL dry methanol, were added DBU (4.00 mL, 54 mmol) and CuI(5.13 g, 27 mmol). The mixture was stirred at RT overnight. The mixturewas diluted with 1.0 liter acetonitrile and stirred vigorously for 1 hr.It was filtered through celite and the filtrate was concentrated andpurified using flash column to give compound 1.5 (8.30 g, 67%). MS foundfor 1.5 C₁₄H₉ClFIN₄OS as (M+H)+ 463.0, 465.0 (Cl pattern).

Step 3:

To a solution of aryl iodide 1.5 (100 mg, 0.22 mmol) and2-hydroxypyridine (42 mg, 0.44 mmol) in 5 mL dry DMSO in a sealed tube,were added 8-hydroxyquinoline (10 mg, 0.007 mmol), CuI (13 mg, 0.07mmol) and Cs₂CO₃ (145 mg, 0.44 mmol). The mixture was stirred in 120° C.bath for overnight. It was then filtered and the filtrate was directlysubjected to reverse phase preparative HPLC to isolate the compound 1.6(66 mg) as a white powder in 68% yield after lyophilization. MS foundfor C₁₉H₁₃ClFN₅O₂S as (M+H)+ 430.0, 432.0 (Cl pattern).

Step 4:

To a solution of compound 1.6 (100 mg, 0.23 mmol) in 1 mL anhydrous DMSOin a sealed tube was added 500 mg piperazine. The mixture was stirred in140° C. bath overnight. It was cooled to RT, and directly subjected toreverse phase HPLC to isolate the title compound as a white powder afterlyophilization. MS found for C₂₃H₂₂ClN₇O₂S (M+H)+ 496.1, 498.1 (Clpattern).

Example 25-Chloro-N-((1-(2-(4-ethylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(2)

The title compound was prepared using conditions similar to thosedescribed in Example 1. MS found for C₂₅H₂₆ClN₇O₂S (M+H)+ 524.1, 526.1(Cl pattern).

Example 35-Chloro-N-((1-(2-(4-isopropylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(3)

The title compound was prepared using conditions similar to thosedescribed in Example 1. MS found for C₂₆H₂₈ClN₇O₂S (M+H)+ 538.1, 540.1(Cl pattern).

Example 45-Chloro-N-((1-(4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(4)

Step 1:

2-Hydroxypyrimidine hydrogenchloride (2.1, 1.50 g, 11.3 mmol) wasstirred in 20 mL dry NMP at RT. To it was added sodium hydride (60% inmineral oil, 0.95 g, 23.5 mmol) in small portions carefully. The mixturewas stirred for 30 min before 4-fluoro-1-nitrobenzene (1.0 mL, 9.4 mmol)was added. The mixture was sent to 80° C. bath and stirred overnight. Itwas concentrated in vacuo and taken into acetonitrile. After vigorouslystirring, the insoluble solid was collected, which was a mixture ofleftover 2-hydroxypyrimidine and 1-(4-nitrophenyl)pyrimidin-2(1H)-one2.2. MS found for C₁₀H₇N₁₀₁ (M+H)⁺ 218.0. This solid (1.27 g, 5.8 mmol)was dissolved in 100 mL ethanol and 30 mL water. To it was addedammonium chloride (3.1 g, 58 mmol) and indium powder (2.6 g, 23 mmol).The mixture was refluxed for 6 hrs. It was concentrated in vacuo,filtered through celite. The solid cake was rinsed with water. Thefiltrate was concentrated and subjected to reverse phase prep HPLC toisolate 1-(4-aminophenyl)pyrimidin-2(1H)-one 2.3. MS found for C₁₀H₉N₃O(M+H)+ 188.1.

Step 2:

1-(4-Aminophenyl)pyrimidin-2(1H)-one (2.3, 250 mg, 1.3 mmol) wasdissolved in 10 mL TFA and stirred in ice bath. To it was added sodiumnitrite (95 mg, 1.3 mmol) in small portions. The mixture was stirred inice bath for 30 min. Sodium azide (260 mg, 4.0 mmol) was dissolved in 2mL water and chilled in ice bath and added to the reaction mixture. Themixture was stirred for 2 hrs and directly subjected to reverse phaseprep HPLC to isolate 1-(4-azidophenyl)pyrimidin-2(1H)-one 2.4. MS foundfor C₁₀H₇N₅O (M+H)+ 214.1.

Step 3:

1-(4-Azidophenyl)pyrimidin-2(1H)-one (2.4, 20 mg, 0.09 mmol) wasdissolved in 5 mL methanol. To it were added5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide (compound 1.4, 18 mg,0.09 mmol), DBU (26 μL, 0.18 mmol) and CuI (17 mg, 0.09 mmol). Themixture was stirred for 2 hrs at RT, diluted with 30 mL acetonitrile,filtered through celite, concentrated in vacuo and subjected to prepHPLC to isolate the title compound. MS found for C₁₈H₁₃ClN₆O₂S (M+H)+413.0, 415.0 (Cl pattern).

Example 55-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(5)

Step 1:

The mixture of 4-iodoacetophenone (3.1, 1.00 g, 4.06 mmol) and glyoxalicacid monohydrate (0.45 g, 4.9 mmol) in 20 mL acetic acid was refluxedfor 18 hrs and concentrated in vacuo. The dry residue was then stirredin 15 mL water to get a slurry material. To it was added carefullyammonium hydroxide (30%) until pH=9 as indicated by pH paper. The pH wascritical for this reaction. Methylhydrazine (0.43 mL) was added, and themixture was sent to 100° C. bath for 3 hrs. Reaction mixture was dilutedwith ethyl acetate. The organic phase was washed with brine, dried,concentrated in vacuo, and purified by flash column using 5% methanol inDCM isocratically to yield compound 3.2 (680 mg, 54%). MS found forC₁₁H₉IN₂O (M+H)+ 313.0.

Step 2:

Compound 3.2 (51 mg, 0.16 mmol),5-chloro-N-(prop-2-ynyl)thiophene-2-carboxamide (compound 1.4, 36 mg,0.18 mmol), L-proline (8 mg, 0.06 mmol), sodium carbonate (7 mg, 0.06mmol), sodium azide (17 mg, 0.24 mmol) and sodium ascorbate (6 mg, 0.03mmol) were mixed in 2 mL DMSO and 0.2 mL water in a sealed tube at RT.To it was added CuSO₄.5H₂O (8 mg, 0.03 mmol). The mixture was stirred in70° C. bath overnight. Reaction was about 70% complete. The titlecompound was isolated through direct reverse phase prep HPLC. MS foundfor C₁₉H₁₅ClN₆O₂S (M+H)+ 427.1, 429.1 (Cl pattern).

Example 65-Chloro-N-((1-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(6)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(4.1, 48 mg, 0.11 mmol, synthesized by procedures similar to those thatwere used to make compound 1.5 described in SCHEME 1),2,4-dimethoxypyrimidin-5-ylboronic acid (4.2, 24 mg, 0.13 mmol),PdCl₂(PPH₃)₂ (38 mg, 0.05 mmol), K₂CO₃ (23 mg, 0.16 mmol) in 1 mLacetonitrile and 1 mL water was degassed using argon stream and heatedin microwave reactor at 125° C. for 15 min. The mixture was filtered anddirectly subjected to reverse phase prep HPLC to isolate the titlecompound. MS found for C₂₀H₁₇ClN₆O₁S (M+H)+ 457.1, 459.1 (Cl pattern).

Example 75-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(9)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(4.1, 100 mg, 0.22 mmol), N-methylhomopiperazine (140 μL, 1.1 mmol), CuI(42 mg, 0.22 mmol), ethylene glycol (25 μL, 0.44 mmol), potassiumphosphate (93 mg, 0.44 mmol) in 2 mL isopropanol in a sealed tube wasstirred for 16 hrs at 120° C. The title compound was isolated directlyfrom the reaction mixture using reverse phase prep HPLC. MS found forC₂₀H₂₃ClN₆OS (M+H)+ 431.1, 433.1 (Cl pattern).

Example 85-Chloro-N-((1-(2′-methoxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(11)

The title compound was prepared according to a procedure similar to thatdescribed in Example 6. MS found for C₂₁H₁₇ClN₄O₂S (M+H)+ 425.1, 427.1(Cl pattern).

Example 95-Chloro-N-((1-(2′-hydroxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(12)

The title compound was prepared according to a procedure similar to thatdescribed in Example 6. MS found for C₂₀H₁₅ClN₄O₂S (M+H)+ 411.1, 413.1(Cl pattern).

Example 105-Chloro-N-((1-(2′-(trifluoromethoxy)biphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(13)

The title compound was prepared according to a procedure similar to thatdescribed in Example 6. MS found for C₂₁H₁₄ClF₃N₄O₂S (M+H)+ 479.0, 481.0(Cl pattern).

Example 115-Chloro-N-((1-(4-(6-chloropyridin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(14)

The title compound was prepared according to a procedure similar to thatdescribed in Example 6. MS found for C₁₉H₁₃Cl₂N₅OS (M+H)+ 430.0, 432.0(Cl pattern).

Example 125-Chloro-N-((1-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(18)

The title compound was prepared according to a procedure similar to thatdescribed in Example 1 using the corresponding substituted aniline. MSfound for C₁₉H₁₈ClN₅O₂S (M+H)+ 416.0, 418.0 (Cl pattern).

Example 135-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(19)

The title compound was prepared according to a procedure similar to thatdescribed in Example 1 using the corresponding substituted aniline. MSfound for C₁₉K₆ClN₅O₂S (M+H)+ 414.0, 416.0 (Cl pattern).

Example 14N-((1-(4-(2-Amino-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(21)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.22 mmol), H-Gly-NHMe.HCl (110 mg, 0.88 mmol), CuI (42 mg,0.22 mmol), N,N′-dimethylethylenediamine (24 μL, 0.22 mmol), cesiumcarbonate (440 mg, 1.4 mmol) in 5 mL dioxane in a sealed tube wasstirred for 15 hrs at 120° C. The title compound was isolated directlyfrom the reaction mixture using reverse phase prep HPLC. MS found forC₁₇H₁₇ClN₆O₂S (M+H)+ 405.1, 407.1 (Cl pattern).

Example 155-Chloro-N-((1-(4-(N-methylpropionamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(24)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.22 mmol), C₂H₅CONHCH₃ (77 μL, 0.88 mmol), CuI (42 mg, 0.22mmol), N,N′-dimethylethylenediamine (24 μL, 0.22 mmol), cesium carbonate(290 mg, 0.88 mmol) in 5 mL dioxane in a sealed tube was stirred for 15hrs at 120° C. The title compound was isolated directly from thereaction mixture using reverse phase prep HPLC. MS found forC₁₈H₁₈ClN₅O₂S (M+H)+ 404.1, 406.1 (Cl pattern).

Example 16

Ethyl4-(4-((5-chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl(methyl)carbamate(25)

The title compound was prepared using a similar procedure as describedin Example 16. MS found for C₁₈H₁₈ClN₅O₃S (M+H)+ 420.1, 422.1 (Clpattern).

Example 175-Chloro-N-((1-(4-(2-methoxy-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(26)

Compound 25 (60 mg, 0.14 mmol) was treated with 2 mL 2N NaOH and 2 mLmethanol at 80° C. for 2 hrs and acidified with 2N HCl. The majorproduct in this reaction,5-chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,was isolated with prep HPLC. MS found for C₁₅H₁₄ClN₅OS (M+H)+ 348.1,350.1. This compound (10 mg, 0.023 mmol) was dissolved in 1 mL DMSO. Toit were added 20 μL DIEA and CH₃OCH₂COCl (25 μL, 0.23 mmol). The mixturewas stirred for 30 min and directly subjected to prep HPLC to isolatethe title compound. MS found for C₁₈H₁₈ClN₅O₁S (M+H)+ 420.1, 422.1 (Clpattern).

Example 185-Chloro-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(27)

5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(34 mg, 0.1 mmol), prepared as shown in Example 17, was dissolved in 10mL methanol and treated with MP-carbonate for 1 hr. The mixture wasfiltered and the filtrate was concentrated in vacuo. The residue wasdissolved in 3 mL pyridine and N,N-dimethylglycine (16 mg, 0.1 mmol) wasadded. The mixture was then stirred in ice bath. POCl₃ (28 μL, 0.3 mmol)was added. The reaction was stirred for 20 min and quenched withmethanol. The mixture was concentrated and directly subjected to prepHPLC to isolate the title compound. MS found for C₁₉H₂₁ClN₆O₂S (M+H)+433.1, 435.1 (Cl pattern).

Example 195-Chloro-N-((1-(4-(N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(28)

The title compound was prepared using a similar procedure as describedin Example 15. MS found for C₁₇H₁₆ClN₅O₂S (M+H)+ 390.1, 392.1 (Clpattern).

Example 205-Chloro-N-((1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(30)

The title compound was prepared according to a procedure similar to thatdescribe in Example 5. MS found for C₁₈H₁₃ClN₆O₂S (M+H)+ 413.1, 415.1(Cl pattern).

Example 215-Chloro-N-((3-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazol-5-yl)methyl)thiophene-2-carboxamide(31)

Step 1:

4-Bromo-2-fluorobenzaldehyde (5.1, 6.64 g, 32.7 mmol) was stirred in 100mL ethanol and 100 mL pyridine. To it was added hydroxylaminehydrochloride (2.27 g, 32.7 mmol). The mixture was stirred at RT for 2hrs. It was concentrated in vacuo to dryness. The residue was thendissolved in 100 mL DMF. To it was added NCS (5.24 g, 39.2 mmol), andthe mixture was stirred for 1 day. It was concentrated in vacuo, takeninto ethyl acetate, washed with brine twice, dried and concentrated invacuo to afford compound 5.2 in quantitative yield. MS found forC₇H₄BrClFNO (M+H)+ 252.0, 254.0.

Step 2:

5-Chloro-2-thiophenecarboxylic acid (5.3, 200 mg, 1.23 mmol) wasdissolved in 10 mL anhydrous DCM. To it were added 1 drop of DMF and0.32 mL oxalyl chloride (3.7 mmol). The mixture was stirred at RT for 3hrs and concentrated in vacuo to dryness. The residue was dissolved in20 mL anhydrous DCM and 2-methylallylamine (0.3 mL, 3.2 mmol) was added.The mixture was stirred for 30 min at RT, concentrated in vacuo, takeninto ethyl acetate, washed with brine three times, dried andconcentrated in vacuo to give compound 5.4 (218 mg, 82%). MS found forC₉H₁₀ClNOS (M+H)+ 216.0, 218.0 (Cl pattern).

Step 3:

The mixture of compound 5.2 (250 mg, 1.0 mmol), compound 5.4 (218 mg,1.0 mmol), and DBU (180 μL, 1.2 mmol) in 10 mL toluene was heated at125° C. in a sealed tube for 1 week. The reaction was still incomplete.It was concentrated in vacuo and subjected to flash column to isolatecompound 5.5 (58 mg, 13%) using 3% methanol in DCM. MS found forC₁₆H₁₃BrClFN₂O₂S (M+H)+ 431.0, 433.0.

Step 4:

Compound 5.5 (58 mg, 0.13 mmol) was dissolved in 6 mL dioxane and 2 mLDMSO in a sealed tube. To it were added 2-hydroxypyridine (29 mg, 0.30mmol), N,N′-dimethylethylenediamine (9 μL, 0.08 mmol), K₃PO₄ (58 mg,0.27 mmol) and CuI (13 mg, 0.07 mmol). The mixture was stirred for 3days at 130° C. It was concentrated and directly subjected to reversephase preparative HPLC to isolate the title compound. MS found forC₂₁H₁₇ClFN₃O₃S (M+H)+ 446.1, 448.1 (Cl pattern).

Example 225-Chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide(32)

Step 1:

Compound 6.1 hydrochloride (1.77 g, 7.9 mmol) and compound 6.2 (1.30 g,7.9 mmol) in 50 mL dioxane were stirred in 60° C. bath overnight. Themixture was concentrated, taken into 300 mL ethyl acetate, washed withbrine three times, dried, and concentrated in vacuo. The residue wasdissolved in 20 mL DMSO and treated with sodium azide (1.04 g, 16 mmol)for 4 hrs. The mixture was diluted with ethyl acetate, washed with brinethree times, dried, concentrated and purified using flash column toisolate compound 6.3 (0.79 g, 34%). MS found for C₁₀H₈BrN₅O (M+H)⁺294.0, 296.0 (Br pattern).

Step 2:

Compound 6.3 (0.79 g, 2.7 mmol) was dissolved in 20 mL ethanol and 20 mLacetic acid, and was treated with iron powder (0.70 g, 13.5 mmol) at100° C. for 30 min. The mixture was diluted with acetonitrile, filteredthrough a celite bed, concentrated and subjected to reverse phasepreparative HPLC to isolate compound 6.4 (40%). MS found for C₁₀H₁₀BrN₃O(M+H)+ 268.0, 270.0 (Br pattern).

Step 3:

Compound 6.4 (120 mg, 0.44 mol) and 5-chloro-2-thiophenecarboxylic acid(110 mg, 0.66 mmol) were dissolved in 15 mL anhydrous DMF. To it wereadded DIEA (310 μL, 1.76 mmol) and PyBOP (460 mg, 0.88 mmol). Themixture was stirred at RT overnight. It was diluted with ethyl acetate,washed with brine three times, dried, concentrated in vacuo and purifiedusing reverse phase preparative HPLC to isolate compound 6.5 (50%). MSfound for C₁₅H₁₁BrClN₃O₂S (M+H)+ 412.0, 414.0.

Step 4:

The title compound was prepared from compound 6.5 using a similarprocedure shown in Step 4 in Example 21. MS found for C₂₀H₁₅ClN₄O₃S(M+H)+ 427.1, 429.1 (Cl pattern).

Example 235-Chloro-N-((2-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,2-dihydropyridin-3-yl)methyl)thiophene-2-carboxamide(33)

Step 1:

The mixture of 1,4-diiodobenzene (7.1, 1.00 g, 3.0 mmol),2-hydroxy-3-methylpyridine (0.50 g, 4.5 mmol), 8-hydroxyquinoline (132mg, 0.9 mmol), K₂CO₃ (0.84 g, 6.0 mmol) and CuI (173 mg, 0.9 mmol) in 12mL DMSO was stirred at 120° C. for 16 hrs in a sealed tube. It wasdiluted with 300 mL ethyl acetate, washed with brine three times, dried,concentrated and purified using flash column to give compound 7.2 (393mg, 42%). MS found for C₁₂H₁₀INO (M+H)+ 312.0.

Step 2:

The mixture of compound 7.2 (393 mg, 1.26 mmol), NBS (247 mg, 1.39 mmol)and AIBN (82 mg, 0.50 mmol) in 20 mL carbon tetrachloride was refluxedovernight. It was concentrated, taken into ethyl acetate, washed withbrine three times, dried, and concentrated in vacuo to dryness. Theresidue was dissolved in 5 mL DMSO and treated with sodium azide (200mg) overnight. It was diluted with ethyl acetate, washed with brinethree times, dried and concentrated in vacuo. The residue was thendissolved in 10 mL ethanol and 10 mL acetic acid and treated with ironpowder (300 mg) at 100° C. for 30 min. The mixture was diluted withacetonitrile, filtered through a celite bed, concentrated and subjectedto reverse phase preparative HPLC to isolate compound 7.3 (20%). MSfound for C₁₂H₁₁1N₂O (M+H)+ 327.0.

Step 3:

Compound 7.3 (80 mg, 0.24 mmol) was dissolved in 10 mL DMF. To it wereadded 5-chloro-2-thiophenecarboxylic acid (60 mg, 0.36 mmol), DIEA (210μL, 1.2 mmol) and PyBOP (250 mg, 0.48 mmol). The mixture was stirredovernight. It was then diluted with ethyl acetate, washed with brinethree times, dried, concentrated and purified by flash column to givecompound 7.4 (90%). MS found for C₁₇H₁₂Cl₁N₂O₂S (M+H)+ 471.0, 473.0.

Step 4:

Compound 7.4 (0.24 mmol) was dissolved in 3 mL DMSO. To it were added2-hydroxypyridine (68 mg, 0.72 mmol), 8-hydroxyquinoline (10 mg, 0.07mmol), cesium carbonate (156 mg, 0.48 mmol) and CuI (14 mg, 0.07 mmol).The mixture was stirred at 120° C. for 16 hrs. It was directly subjectedto reverse phase preparative HPLC to isolate the title compound. MSfound for C₂₂H₁₆ClN₃O₃S (M+H)+ 438.1, 440.1 (Cl pattern).

Example 245-Chloro-N-((6-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,6-dihydropyridin-3-yl)methyl)thiophene-2-carboxamide(34)

The title compound was prepared according to a procedure similar to thatdescribed in Example 23. MS found for C₂₂H₁₆ClN₃O₃S (M+H)+ 438.1, 440.1(Cl pattern).

Example 255-Chloro-N-((1-methyl-2-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(35)

To a solution of potassium acetate (0.860 g, 8.78 mmol) in H₂O (3 mL),3,3-dibromo-1,1,1-trifluoroacetone (1.10 g, 4.07 mmol) was added. Thesolution was heated at 100° C. for 30 min. After being cooled to roomtemperature, a solution of 4-iodobenzaldehyde (0.860 g, 3.71 mmol) inMeOH (4 mL) and THF (4 mL) was added, followed by conc. NH₄OH (8 mL).The mixture was stirred at room temperature overnight. Water and EtOAcwere added. The organic layer was separated, dried over Na₂SO₄,concentrated in vacuo to give2-(4-iodophenyl)-4-(trifluoromethyl)-1H-imidazole as a solid (1.34 g).

The mixture of 2-(4-iodophenyl)-4-(trifluoromethyl)-1H-imidazoleprepared above (1.34 g) in 5N aq. NaOH (12 mL) was heated at 90° C. for2 h. It was filtered. The filtrate was neutralized with 6 N HClcarefully to pH 6-7. The product was extracted with nBuOH. The nBuOHsolution was then concentrated in vacuo to give2-(4-iodophenyl)-1H-imidazole-4-carboxylic acid as a solid (0.512 g).

To a mixture of 2-(4-iodophenyl)-1H-imidazole-4-carboxylic acid preparedabove (257 mg, 0.818 mmol) and NaH (60% suspension, washed with hexane,82 mg, 2.1 mmol) in DMF (8 mL) was added iodomethane (0.130 mL, 2.1mmol). The mixture was heated at 50° C. for 2 h. More iodomethane (0.100mL) was added to the reaction mixture. After being stirred at 50° C. foran additional 2 h, water and EtOAc were added. The organic layer wasseparated, dried over Na₂SO₄, concentrated in vacuo to give methyl2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate (152 mg). MS 342.8(M+H).

To a suspension of methyl2-(4-iodophenyl)-1-methyl-1H-imidazole-4-carboxylate prepared above (72mg, 0.21 mmol) in toluene (4 mL), LiAlH₄ (61 mg, 1.6 mmol) was added.

The mixture was heated at 110° C. overnight. After being cooled to roomtemperature, EtOAc (15 mL) and 1N aq. NaOH (15 mL) were added. Themixture was filtered through celite.

The organic layer was separated, dried over Na₂SO₄, concentrated invacuo to give (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanol (46mg). MS 315.0 (M+H).

A solution of (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methanolprepared above (46 mg, 0.15 mmol) in SOCl₂ (2 mL) was stirred at roomtemperature for 15 min. It was concentrated in vacuo to give a residue,which was then partitioned between EtOAc and 5% aq. NaHCO₃. The organicphase was separated, dried over Na₂SO₄, concentrated in vacuo.

The residue was dissolved in DMF (2 mL). To the solution, NaN₃ (70 mg,1.1 mmol) was added. After the mixture was stirred at room temperaturefor 2 days, water and EtOAc were added. The organic layer was separated,dried over Na₂SO₄, concentrated in vacuo to give(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azide (46 mg). MS340.0 (M+H).

A mixture of (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl azideprepared above (46 mg, 0.14 mmol) and Ra—Ni (50% slurry in H₂O, 100 mg)in MeOH (5 mL) was hydrogenated under balloon H₂ for 1 h. It wasfiltered. The filtrate was concentrated in vacuo to give(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine (42 mg). MS314.0 (M+H).

To a solution of 5-chloro-thiophene-2-carboxylic acid (23 mg, 0.14mmol), (2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl amine preparedabove (21 mg, 0.067 mmol) and TEA (0.050 mL, 0.36 mmol) in DMF (2 mL)was added BOP (70 mg, 0.16 mmol). The mixture was stirred at roomtemperature overnight. It was then purified by HPLC to give5-chloro-N-((2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(14 mg). MS 457.9 and 459.9 (M+H).

A mixture of5-chloro-N4(2-(4-iodophenyl)-1-methyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamideprepared above (14 mg, 0.031 mmol), 2-hydroxypyridine (14 mg, 0.15mmol), 8-hydroxyquinoline (14 mg, 0.097 mmol) and K₂CO₃ (30 mg, 0.22mmol) in DMSO (0.5 mL) was degassed with Argon before being charged withCuI (9 mg, 0.047 mmol). The mixture in a sealed tube was heated at 130°C. overnight. It was then purified by HPLC to give the titled compound(2 mg). MS 425.1 and 427.1 (M+H, Cl pattern).

Example 265-Chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(36)

A mixture of 1,4-diiodobenzene 9.1 (4.00 g, 12.1 mmol),4-(hydroxymethyl)imidazole 9.2 (1.20 g, 12.2 mmol), 8-hydroxyquinoline(0.176 g, 1.21 mmol) and K₂CO₃ (1.69 g, 12.2 mmol) in DMSO (12 mL) wasdegassed before being charged with CuI (0.230 g, 1.21 mmol). The mixturein a sealed tube was heated at 130° C. overnight. Water and EtOAc wereadded. The mixture was filtered. The organic layer was separated, thenapplied to a silica gel column, which was eluted with 0-5% MeOH inCH₂Cl₂ to give (1-(4-iodophenyl)-1H-imidazol-4-yl)methanol 9.3 (0.810 g)and its isomer (1-(4-iodophenyl)-1H-imidazol-5-yl)methanol 9.4. MS 301.2(M+H).

Step 2:

The compound 4-hydroxymethyl 1-(4-iodophenyl)imidazole 9.3 (0.810 g,2.70 mmol) was dissolved in SOCl₂ (6 mL). The solution was stirred atroom temperature for 15 min. It was then concentrated in vacuo. Theresidue was partitioned between EtOAc and 5% aq. NaHCO₃. The organiclayer was separated, dried over Na₂SO₄, concentrated in vacuo to give4-(chloromethyl)-1-(4-iodophenyl)-1H-imidazole 9.5 as a solid (0.780 g).MS 318.9 and 320.9 (M+H, Cl pattern)

Step 3:

The compound 4-(chloromethyl)-1-(4-iodophenyl)-1H-imidazole 9.5 (0.780g, 2.45 mmol) was dissolved in DMF (10 mL). To the solution, NaN₃ (0.520g, 8.00 mmol) was added. After being stirred at room temperatureovernight, water and EtOAc were added. The organic layer was separated,dried over Na₂SO₄, concentrated in vacuo to give4-(azidomethyl)-1-(4-iodophenyl)-1H-imidazole 9.6 as a solid (0.725 g).MS 326.0 (M+H).

Step 4:

A solution of 4-(azidomethyl)-1-(4-iodophenyl)-1H-imidazole 9.6 (0.725g, 2.23 mmol) over Ra—Ni (50% aq. slurry, 300 mg) in MeOH (12 mL) washydrogenated under balloon H₂ for 3 h. The mixture was filtrated throughCELITE. The filtrate was concentrated in vacuo to give(1-(4-iodophenyl)-1H-imidazol-4-yl)methanamine 9.7 as a solid (0.603 g).MS 300.0 (M+H).

Step 5:

To a mixture of 5-chlorothiophene-2-carboxylic acid (0.346 g, 2.13mmol), (1-(4-iodophenyl)-1H-imidazol-4-yl)methanamine 9.7 (0.578 g, 1.93mmol) and TEA (0.670 mL, 4.82 mmol) in DMF (10 mL), BOP (1.03 g, 2.33mmol) was added. The mixture was then stirred at room temperatureovernight. Water and EtOAc were added. The organic layer was separated,washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated in vacuo to givethe title compound as a solid (0.832 g). MS found for C₁₅H₁₁ClIN₃OS:443.9 and 445.9 ((M+H)+, Cl pattern).

Example 275-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(37)

Step 1:

The mixture of 4-iodoacetophenone (1.00 g, 4.06 mmol) and glyoxalic acidmonohydrate (0.45 g, 4.9 mmol) in 20 mL acetic acid was refluxed for 18hrs before concentrated in vacuo. The dry residue was then stirred in 15mL water to form a slurry material. To it was added carefully withammonium hydroxide (30%) until pH 9 as indicated by pH paper. The pH wascritical for this reaction. Methylhydrazine (0.43 mL) was added, and thereaction was sent to 100° C. bath for 3 hrs before the mixture wasdiluted with ethyl acetate. The organic phase was washed with brine,dried, concentrated in vacuo, and purified by flash column using 5%methanol in DCM isocratically to yield6-(4-iodophenyl)-2-methylpyridazin-3(2H)-one (680 mg, 54%). MS found forC₁₁H₉IN₂O (M+H)+ 313.0.

Step 2:

The above-prepared compound (145 mg, 0.49 mmol) was dissolved in 10 mLDMSO in a sealed tube. To it were added (1H-imidazol-4-yl)methanolhydrochloride (134 mg, 1.0 mmol), cesium carbonate (815 mg, 2.5 mmol),CuI (48 mg, 0.25 mmol) and 8-hydroxyquinoline (37 mg, 0.25 mmol). Themixture was stirred at 130° C. for 17 hrs. It was filtered and subjectedto prep HPLC to isolate6-(4-(4-(hydroxymethyl)-1H-imidazol-1-yl)phenyl)-2-methylpyridazin-3(2H)-one(95 mg, 69%). MS found for C₁₅H₁₄N₄O₂ (M+H)+ 283.1.

Step 3:

The above-prepared compound (95 mg, 0.34 mmol) was stirred in 4 mLacetonitrile at RT. To it was added 4 mL thionyl chloride and themixture was stirred for 30 min. It was concentrated in vacuo. Theresidue was then dissolved in 5 mL DMSO and 5 mL ammonia hydroxide wasadded. The mixture was stirred at 75° C. in a sealed tube for 30 min. Itwas concentrated in vacuo and subjected to prep HPLC to isolate6-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)-2-methylpyridazin-3(2H)-one.MS found for C₁₅H₁₅N₅O (M+H)+ 282.1.

Step 4:

The above-prepared compound was dissolved in 40 mL methanol and treatedwith MP-carbonate (10 eq.). The mixture was gently stirred for 1 hr andfiltered. The filtrate was concentrated in vacuo to give thecorresponding free amine (47 mg, 0.17 mmol). It was dissolved in 2 mLDMF. To it was added DIEA (36 μL, 0.20 mmol) and the mixture was stirredat RT. In the meantime, 5-chlorothiophene-2-carboxylic acid (32 mg, 0.20mmol) was dissolved in 2 mL dry DMF. To it were added DIEA (36 μL, 0.20mmol) and HATU (76 mg, 0.20 mmol). The mixture was stirred for 10 min.It was added to the stirred solution of the free amine in DMF. Themixture was stirred for 2 hrs and subjected to preparative HPLC toisolate the title compound. MS found for C₂₀H₁₆ClNO₂S (M+H)+ 426.1,428.1 (Cl pattern).

Example 285-Chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(38)

To a solution of diisopropylamine (1.42 mL, 10 mmol) in THF (10 mL) at0° C. was added nBuLi (2.5 M, 4.25 mL, 10.6 mmol) dropwise. Afterstirring at 0° C. for 45 min, a solution of 2-methoxypyridine (0.96 mL,9.2 mmol) in THF (5 mL) was added, and the mixture was stirred for anadditional 1 h before B(OiPr)₃ (2.54 mL, 11 mmol) was added. 30 minlater, H₂O was added to quench the reaction, the THF was removed invacuo and the aqueous layer was extracted with ether. The aqueous layerwas separated, acidified with 48% HBr to pH=4, the resultingprecipitates were collected by filtration to yield2-methoxypyridine-3-ylboronic acid (0.46 g, 40%).

A mixture of5-chloro-N-((1-(4-iodophenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(0.044 g, 0.1 mmol), 2-methoxypyridine-3-ylboronic acid (0.016 g, 0.11mmol) and Pd(PPh₃)₂Cl₂ (0.007 g, 0.01 mmol) in p-dioxane (0.7 mL) waspurged with Argon for 5 min. A degassed aqueous solution of Na₂CO₃ (1M,0.3 mL) was added. After being heated at 100° C. for 2 h, the mixturewas cooled to room temperature, and purified by preparative HPLC toyield5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(MS 425.0, 427.0 (M+H), Cl pattern).

Example 295-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(39)

To a solution of5-chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(0.01 g, 0.024 mmol) in AcCN (1 mL) was added NaI (0.011 g, 0.072 mmol)and TMSCl (0.045 mL, 0.36 mmol). After heating at 80° C. for 90 min, thereaction mixture was cooled to room temperature, and purified bypreparative HPLC to yield5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(MS 411.0, 413.0 (M+H) Cl pattern).

Example 305-Chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(40)

To a solution of5-chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(0.02 g, 0.05 mmol) in DMF (0.5 mL) was added Cs₂CO₃ (0.049 g, 0.15mmol) and MeI (0.01 mL, 0.15 mmol). After stirring for 30 min at ambienttemperature, the mixture was purified by preparative HPLC to give5-chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(MS 425.1, 427.1 (M+H) Cl pattern).

Example 314-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)benzamide(43)

To a solution of 4-chlorobenzoic acid (40 mg, 0.26 mmol) andtriethylamine (0.150 mL, 1.08 mmol) in DMF (2 mL), BOP (135 mg, 0.30mmol) was added. After 5 min of stirring,1-(4-(4-(aminomethyl)-1H-imidazol-1-yl)phenyl)pyridin-2(1H)-onehydrochloride (53 mg, 0.18 mmol) was added. The mixture was stirred atroom temperature for 2 h. It was then purified by HPLC to give thetitled compound (25 mg). MS 405.1 and 407.1 (M+H, Cl pattern).

Example 325-Chloro-N-((1-(5-(2-oxopyridin-1(2H)-yl)pyridin-2-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(45)

Step 1:

A mixture of 5-bromo-2-fluoropyridine (630 mg, 3.58 mmol),4-imidazolecarboxaldehyde (355 mg, 3.70 mmol) and K₂CO₃ (1.00 g, 7.25mmol) in DMF (10 mL) was stirred at 70° C. overnight. After being cooleddown, H₂O was added to induce precipitation. The precipitate wascollected and dried on vacuum to give1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde (738 mg).

Step 2:

To a suspension of 1-(5-bromopyridin-2-yl)-1H-imidazole-4-carbaldehyde(730 mg, 2.90 mmol) in MeOH (10 mL) at room temperature was added NaBH₄(134 mg, 3.53 mmol). The mixture was stirred for 30 min, during whichtime the suspension became clear. The solvent was removed in vacuo. Theresidue was partitioned between H₂O and EtOAc. The organic phase wasseparated, washed with 5% NaHCO₃, dried over Na₂SO₄, concentrated invacuo to give (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol as asolid (520 mg).

Step 3:

To a suspension of (1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanol(520 mg, 2.05 mmol) in CH₃CN (5 mL) at room temperature was added SOCl₂(2.5 mL). With the addition, the suspension became clear. After 10 minof stirring, the mixture was concentrated in vacuo. The residue wasdissolved in DMF (12 mL), and NaN₃ (565 mg, 8.69 mmol) was added. Themixture was stirred at room temperature overnight. H₂O and EtOAc wereadded. The organic phase was separated, washed with 5% NaHCO₃, driedover Na₂SO₄, concentrated in vacuo to give2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500 mg).

Step 4:

A mixture of 2-(4-(azidomethyl)-1H-imidazol-1-yl)-5-bromopyridine (500mg, 1.79 mmol) and iron powder (767 mg, 13.7 mmol) in EtOH (8 mL) andHOAc (6 mL) was heated at reflux for 2 h. It was filtered throughcelite. The filtrate was concentrated in vacuo. The residue waspartitioned between 5% NaHCO₁ and EtOAc. The biphasic solution wasfiltered. The EtOAc phase was separated, dried over Na₂SO₄, andconcentrated in vacuo to give(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg).

Step 5:

To a solution of 5-chloro-2-thiophenecarboxylic acid (195 mg, 1.20 mmol)and triethylamine (0.400 mL, 2.87 mmol) in DMF (5 mL), BOP (550 mg, 1.24mmol) was added.

After 5 min of stirring, a solution of(1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methanamine (253 mg, 1.00mmol) in DMF (5 mL) was added. The mixture was stirred at roomtemperature overnight. H₂O and EtOAc were added. The organic phase wasseparated, washed with 5% NaHCO₃, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by HPLC to giveN-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(85 mg).

Step 6:

A mixture ofN-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(42 mg, 0.11 mmol), 2-hydroxypyridine (40 mg, 0.42 mmol),N,N′-dimethylethylenediamine (0.035 mL, 0.32 mmol) and K₂CO₃ (52 mg,0.38 mmol) in DMSO (1 mL) and dioxane (1 mL) was degassed with Argonbefore being charged with CuI (23 mg, 0.12 mmol). The mixture was heatedat 110° C. overnight in a sealed tube. It was then purified by HPLC togive the title compound (3 mg). MS found for C₁₉H₁₄ClN₅O₂S: 412.2 and414.2 (M+H, Cl pattern).

Example 335-Chloro-N-((1-(6-(2-oxopyridin-1(2H)-yl)pyridin-3-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide(46)

A mixture of 3-amino-6-bromopyridine (865 mg, 5.00 mmol),2-hydroxypyridine (475 mg, 5.00 mmol), N,N′-dimethylethylenediamine(0.215 mL, 2.00 mmol) and K₂CO₃ (1.38 g, 10.0 mmol) in dioxane (8 mL)was degassed with Argon before being charged with CuI (190 mg, 1.00mmol). The mixture in a sealed tube was heated at 110° C. overnight.After being cooled down, H₂O and nBuOH were added. The organic phase wasseparated, and concentrated in vacuo to give1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316 mg).

To a solution of 1-(5-aminopyridin-2-yl)pyridin-2(1H)-one (316 mg, 1.69mmol) in concentrated HCl (8 mL) cooled in an ice bath, a solution ofNaNO₂ (117 mg, 1.69 mmol) in H₂O (3 mL) was added dropwise. After 30 minof stirring, NaI (1.03 g, 6.87 mmol) in H₂O (4 mL) was added. Themixture was stirred at 0° C. for 1 h. It was then allowed to warm up toroom temperature and stirred at room temperature overnight. The mixturewas extracted with EtOAc. The EtOAc solution was washed with 5% NaHCO₃,then with Na₂S₂O₃, dried over Na₂SO₄, and concentrated in vacuo to give1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (189 mg).

A mixture of 1-(5-iodopyridin-2-yl)pyridin-2(1H)-one (75 mg, 0.25 mmol),N-((1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (60 mg,0.17 mmol), 8-hydroxyquinoline (10 mg, 0.069 mmol) and K₂CO₃ (100 mg,0.72 mmol) in DMSO (1 mL) was degassed with Argon before being chargedwith CuI (19 mg, 0.10 mmol). The mixture in a sealed tube was heated at130° C. overnight. It was then purified by HPLC to give the titlecompound (11 mg). MS found for C₁₉H₁₄ClN₅O₂S: 412.0 and 414.0 (M+H, Clpattern).

Example 345-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-5-yl)methyl)thiophene-2-carboxamide(51)

The compound 10.1 was prepared from(1-(4-iodophenyl)-1H-imidazol-5-yl)methanol (Compound 9.4, prepared asshown in Example 26) using a similar procedure as described in Example26. The title compound was prepared from compound 10.1 under conditionssimilar to that described in step 4 of Example 1. MS found forC₂₀H₁₆ClN₅O₂S (M+H)+ 426.1 (Cl pattern).

Example 355-Chloro-N-((1-(2-fluoro-4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(54)

The title compound was prepared using a similar procedure as describedin EXAMPLE 4. MS found for C₁₈H₁₂ClFN₆O₂S (M+H)+ 431.0, 433.0 (Clpattern).

Example 365-Chloro-N-((1-(2-fluoro-4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(55)

The title compound was prepared using a similar procedure as describedin Example 4. MS found for C₁₈H₁₂ClFN₆O₂S (M+H)+ 431.0, 433.0 (Clpattern).

Example 375-Chloro-N-((1-(2-fluoro-4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(57)

The title compound was prepared using a similar procedure as describedin Example 4. MS found for C₁₈H₁₆ClFN₆O₂S (M+H)+ 435.0, 437.0 (Clpattern).

Example 385-Chloro-N-((1-(2-fluoro-4-(3-methyl-2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(58)

The title compound was prepared using a similar procedure as describedin Example 4. MS found for C₁₉H₁₈ClFN₆O₂S (M+H)+ 449.0, 451.0 (Clpattern).

Example 395-Chloro-N-((1-(2-fluoro-4-(2-oxopiperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(59)

The title compound was prepared using a similar procedure as describedin Example 4. MS found for C₁₉H₁₇ClFN₅O₂S (M+H)+ 434.1, 436.1 (Clpattern).

Example 405-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(60)

The title compound was prepared using a similar procedure as describedin Example 4. MS found for C₁₉H₁₃ClFN₅O₂S (M+H)+ 430.0, 432.0 (Clpattern).

Example 415-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(61)

5-Chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(306 mg, 0.69 mmol, prepared using a similar procedure as described inExample 4) was stirred in 40 mL DCM as a slurry. BBr₃ (200 μL, 2.1 mmol)was added. The mixture was stirred for 2 hrs and concentrated in vacuo.The residue was dissolved in 1 mL and 5 mL DMSO and subjected to prepHPLC to isolate the title compound as a white powder. MS found forC₁₉H₁₄ClN₅O₃S (M+H)+ 428.1, 430.1 (Cl pattern).

Example 425-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(62)

5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(30 mg, 0.07 mmol, prepared as shown in EXAMPLE 61) was dissolved in 2mL DMSO. To it were added cesium carbonate (69 mg, 0.21 mmol) and2-bromoethanol (10 μL, 0.14 mmol). The mixture was stirred in a sealedtube at 70° C. for 30 min, and was directly subjected to reverse phaseprep HPLC to isolate the title compound. MS found for C₂₁H₁₈ClN₅O₄S(M+H)+ 472.1, 474.1 (Cl pattern).

Example 435-Chloro-N-((1-(4-(3-(2-methoxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(63)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₂H₂₀ClN₅O₄S (M+H)+ 486.1, 488.1 (Clpattern).

Example 445-Chloro-N-((1-(4-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(64)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₃H₂₃ClN₆O₃S (M+H)+ 499.1, 501.1 (Clpattern).

Example 455-Chloro-N-((1-(4-(3-(2-(dimethyl(dimethylamino)amino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(65)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₇H₃₃ClN₇O₃S (M+H)+ 570.1, 572.1 (Clpattern).

Example 465-Chloro-N-((1-(4-(2-oxo-3-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(66)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₆H₂₇ClN₆O₁S (M+H)+ 539.1, 541.1 (Clpattern).

Example 475-Chloro-N-((1-(4-(2-oxo-3-(3-(piperidin-1-yl)propoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(67)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₇H₂₉ClN₆O₃S (M+H)+ 553.1, 555.1 (Clpattern).

Example 485-Chloro-N-((1-(4-(3-(2-(methylthio)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(68)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₂H₂₀ClN₅O₃S₂ (M+H)+ 502.1, 504.1 (Clpattern).

Example 495-Chloro-N-((1-(4-(3-(2-(methylsulfinyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(69)

To a solution of Example 48 in a 2:1 mixture of methanol and water wasadded 1.0 equivalent of oxone. The mixture was stirred at roomtemperature for 10 min and directly subjected to reverse phase HPLC toisolate the title compound as a white powder after lyophilization. MSfound for C₂₂H₂₀ClN₅O₄S₂ (M+H)+ 518.1, 520.1 (Cl pattern).

Example 505-Chloro-N-((1-(4-(3-(2-(methylsulfonyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(70)

To a solution of Example 48 in a 2:1 mixture of methanol and water wasadded 3 equivalent of oxone. The mixture was stirred at room temperaturefor 1 hr and directly subjected to reverse phase HPLC to isolate thetitle compound as a white powder after lyophilization. MS found forC₂₂H₂₀ClN₅O₅S₂ (M+H)+ 534.1, 536.1 (Cl pattern).

Example 515-Chloro-N-((1-(4-(3-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(71)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₅H₂₅ClN₆O₄S (M+H)+ 541.1, 543.1 (Clpattern).

Example 52N-((1-(4-(3-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(72)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₄H₂₀ClN₇O₁S (M+H)+ 522.1, 524.1 (Clpattern).

Example 535-Chloro-N-((1-(4-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(73)

The title compound was prepared using a similar procedure as describedin Example 42. MS found for C₂₄H₂₀ClN₇O₃S (M+H)+ 522.1, 524.1 (Clpattern).

Example 545-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(74)

The title compound was prepared using a similar procedure as describedin Example 41 from5-chloro-N-((1-(4-(5-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(prepared using a similar procedure as described in Example 4). MS foundfor C₁₉H₁₄ClN₅O₃S (M+H)+ 428.1, 430.1 (Cl pattern).

Example 555-Chloro-N-((1-(4-(5-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(75)

The title compound was prepared using the same procedure described inExample 42 from5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(prepared as shown in EXAMPLE 74). MS found for C₂₃H₂₃ClN₆O₃S (M+H)+499.1, 501.1 (Cl pattern).

Example 56N-((1-(4-(4-Amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(79)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.23 mmol), cytosine (100 mg, 0.90 mmol), CuI (23 mg, 0.12mmol), 8-hydroxyquinoline (18 mg, 0.12 mmol), potassium carbonate (96mg, 0.69 mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrs at120° C. The title compound was isolated directly from the reactionmixture using reverse phase prep HPLC. MS found for C₁₈H₁₄ClN₇O₂S (M+H)+428.1, 430.1 (Cl pattern).

Example 575-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(80)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.23 mmol), uracil (100 mg, 0.90 mmol), CuI (23 mg, 0.12 mmol),8-hydroxyquinoline (18 mg, 0.12 mmol), potassium carbonate (96 mg, 0.69mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrs at 120° C.The title compound was isolated directly from the reaction mixture usingreverse phase prep HPLC. MS found for C₁₈H₁₃ClN₆O₃S (M+H)+ 429.1, 431.1(Cl pattern).

Example 58N-((1-(4-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide(81)

The title compound was prepared using a similar procedure as describedin Example 57. MS found for C₁₈H₁₃ClFN₇O₂S (M+H)+ 446.1, 448.1 (Clpattern).

Example 595-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(82)

The title compound was prepared using a similar procedure as describedin Example 57. MS found for C₁₉H₁₅ClN₆O₃S (M+H)+ 443.1, 445.1 (Clpattern).

Example 605-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(83)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.22 mmol), 4-N-Boc-2-oxo-piperazine (88 mg, 0.44 mmol), CuI(13 mg, 0.066 mmol), N,N′-dimethylethylenediamine (8 μL, 0.066 mmol),potassium carbonate (61 mg, 0.44 mmol) in 5 mL dioxane in a sealed tubewas stirred for 2 days at 120° C. The mixture was diluted with ethylacetate (200 mL). It was washed with brine, dried, and concentrated invacuo. The residue was treated with neat TFA for 15 min and directlysubjected to prep HPLC to isolate the title compound. MS found forC₁₈H₁₇ClN₆O₂S (M+H)+ 417.1, 419.1 (Cl pattern).

Example 615-Chloro-N-((1-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(84)

5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(24 mg, 0.06 mmol, prepared as shown in Example 60) was stirred in 2 mLacetic acid at RT. To it was added formaldehyde (37% in water, 22 μL,0.3 mmol). The mixture was stirred for 10 min. NaBH₃CN (30 mg, 0.48mmol) was added. The reaction was allowed for 10 min, and directlysubjected to reverse phase prep HPLC to isolate the title compound. MSfound for C₁₉H₁₉ClN₆O₂S (M+H)+ 431.1, 433.1 (Cl pattern).

Example 625-Chloro-N-((1-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(85)

The title compound was prepared using a similar procedure as describedin Example 61. MS found for C₂₁H₂₃ClN₆O₂S (M+H)+ 459.1, 461.1 (Clpattern).

Example 634-(4-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-oxopiperazine-1-carboxamide(86)

5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(23 mg, 0.055 mmol, prepared as shown in Example 60) was dissolved in 2mL water and 0.5 mL DMSO. To it was added KOCN (23 mg, 0.28 mmol). Themixture was stirred at RT over the weekend. The title compound was themajor product in this reaction and was isolated using direct reversephase prep HPLC. MS found for C₁₉H₁₈ClN₇O₃S (M+H)+ 460.1, 462.1 (Clpattern).

Example 645-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(87)

The mixture of5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.22 mmol), 2,3-pyrazinediol (74 mg, 0.66 mmol), CuI (21 mg,0.11 mmol), 8-hydroxyquinoline (16 mg, 0.11 mmol), potassium carbonate(152 mg, 1.1 mmol) in 2 mL DMSO in a sealed tube was stirred for 15 hrsat 130° C. The title compound was isolated directly from the reactionmixture using reverse phase prep HPLC. MS found for C₁₈H₁₃ClN₆O₃S (M+H)+429.1, 431.1 (Cl pattern).

Example 655-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide(108)

A solution of 4-iodoaniline (0.684 g, 3.12 mmol) and2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (90%, 0.492 mL, 3.12 mmol)in HOAc (10 mL) was stirred at 90° C. for 1 h. The solvent was removedin vacuo. The residue was partitioned between EtOAc and H₂O. The organicphase was separated, washed with 5% NaHCO₃, dried over Na₂SO₄, andconcentrated in vacuo to give 1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde(0.927 g).

To a suspension of 1-(4-iodophenyl)-1H-pyrrole-3-carbaldehyde (927 mg,3.12 mmol) in MeOH (15 mL) at room temperature was added NaBH₄ (142 mg,3.74 mmol). The mixture was stirred at room temperature for 10 min,during which time the suspension became clear. The solvent was removedin vacuo. The residue was partitioned between H₂O and EtOAc. The organicphase was separated, washed with 1N HCl, 1N NaOH and brine, dried overNa₂SO₄, and concentrated in vacuo to give the alcohol (877 mg).

To a solution of the alcohol (220 mg, 0.736 mmol) and diphenylphosphoryl azide (0.174 mL, 0.808 mmol) in THF (5 mL) was added DBU(0.110 mL, 0.737 mmol). The mixture was stirred at room temperatureovernight. It was concentrated in vacuo. The residue was purified byHPLC to give the azide (124 mg).

A mixture of the azide (124 mg, 0.38 mmol) and Ra—Ni (50% aq. slurry,˜100 mg) in MeOH (8 mL) was hydrogenated under balloon H₂ for 3 h. Itwas then filtered through celite, and filtrate was concentrated in vacuoto give (1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg).

To a solution of 5-chloro-thiophene-2-carboxylic acid (60 mg, 0.37 mmol)and TEA (0.102 mL, 0.73 mmol) in DMF (4 mL) was added BOP (196 mg, 0.44mmol). After 10 min of stirring, the solution was added to a sample of(1-(4-iodophenyl)-1H-pyrrol-3-yl)methanamine (91 mg, 0.31 mmol) in aflask. The mixture was stirred at room temperature overnight. H₂O wasadded to induce precipitation. The resulting precipitate was collectedand dried on vacuum to give5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide(118 mg).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide(118 mg, 0.27 mmol), 2-hydroxypyridine (50 mg, 0.53 mmol),8-hydroxyquinoline (14 mg, 0.097 mmol) and K₂CO₃ (120 mg, 0.87 mmol) inDMSO (2 mL) was degassed with Argon before being charged with CuI (19mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C. for 4h. It was then purified by HPLC to give the titled compound (20 mg). MS410.0 and 412.0 (M+H, Cl pattern).

Example 665-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(109)

A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol), 4-methylpyrazole(0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g, 1.21 mmol) and K₂CO₃(1.69 g, 12.2 mmol) in DMSO (12 mL) was degassed before being chargedwith CuI (0.310 g, 1.63 mmol). The mixture in a sealed tube was heatedat 130° C. overnight. Water and EtOAc were added. The mixture wasfiltered. The organic layer was separated, then applied to a silica gelcolumn, which was eluted with hexane, then with 5% EtOAc in hexane togive 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g).

A mixture of 1-(4-iodophenyl)-4-methyl-1H-pyrazole (1.70 g, 5.99 mmol),NBS (1.38 g, 7.75 mmol) and AIBN (0.30 g, 1.83 mmol) in CCl₄ (25 mL) washeated at reflux for 1 hr. After being cooled to room temperature, theupper clear solution was decanted out and concentrated in vacuo. Theresidue was dissolved in DMF (10 mL), NaN₃ (0.934 g, 14.3 mmol) wasadded. The mixture was stirred at room temperature overnight. H₂O andEtOAc were added. The organic phase was separated, dried over Na₂SO₄,concentrated in vacuo. The residue was purified by a silica gel column,eluted with hexane, then with 5% EtOAc in hexane to give4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.70 g).

A mixture of 4-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (530 mg, 1.63mmol) and Ra—Ni (50% aq. slurry, 200 mg) in MeOH (3 mL) was hydrogenatedunder balloon H₂ for 1 hr. It was filtered through celite. The filtratewas concentrated in vacuo to give(144-iodophenyl)-1H-pyrazol-4-yl)methanamine (396 mg).

To a solution of 5-chloro-thiophene-2-carboxylic acid (237 mg, 1.46mmol), (1-(4-iodophenyl)-1H-pyrazol-4-yl)methanamine (396 mg, 1.32 mmol)and TEA (0.500 mL, 3.59 mmol) in DMF (10 mL), BOP (828 mg, 1.87 mmol)were added. The mixture was stirred at room temperature overnight. H₂Oand EtOAc were added. The organic phase was separated, washed with 5%NaHCO₃, dried over Na₂SO₄, concentrated in vacuo to give5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(462 mg).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(200 mg, 0.451 mmol), 2-hydroxypyridine (85 mg, 0.90 mmol),8-hydroxyquinoline (30 mg, 0.21 mmol) and K₂CO₃ (247 mg, 1.79 mmol) inDMSO (2 mL) was degassed with Argon before being charged with CuI (43mg, 0.22 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give the title compound (60mg). MS 411.0 and 413.0 (M+H, Cl pattern).

Example 675-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(110)

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(100 mg, 0.225 mmol), 1-methylhomopiperazine (0.100 mL, 0.81 mmol),ethylene glycol (0.025 mL, 0.45 mmol) and K₃PO₄ (100 mg, 0.47 mmol) inisopropanol (1 mL) was degassed with Argon before being charged with CuI(20 mg, 0.11 mmol). The mixture in a sealed tube was heated at 85° C.overnight. It was then purified by HPLC to give the title compound (5mg). MS 430.0 and 432.0 (M+H, Cl pattern).

Example 685-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(111)

To a solution of glycinamide hydrochloride (1.10 g, 10.0 mmol) in 5 NNaOH (6 mL) at room temperature, glyoxal (40% in H₂O, 1.5 mL, 13.1 mmol)was added. The solution was stirred at room temperature overnight. Theproduct was extracted from the aqueous solution with nBuOH, and nBuOHextract was concentrated in vacuo to give 2-hydroxypyrazine as a whitesolid (0.20 g).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide(75 mg, 0.17 mmol), 2-hydroxypyrazine (43 mg, 0.45 mmol),8-hydroxyquinoline (15 mg, 0.10 mmol) and K₂CO₃ (100 mg, 0.72 mmol) inDMSO (1 mL) was degassed with Argon before being charged with CuI (19mg, 0.10 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give the title compound (10mg). MS 412.0 and 414.0 (M+H, Cl pattern).

Example 695-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide(112)

A mixture of 1,4-diiodobenzene (4.00 g, 12.1 mmol), 3-methylpyrazole(0.972 g, 12.1 mmol), 8-hydroxyquinoline (0.176 g, 1.21 mmol) and K₂CO₃(1.69 g, 12.2 mmol) in DMSO (12 mL) was degassed before being chargedwith CuI (0.230 g, 1.21 mmol). The mixture in a sealed tube was heatedat 130° C. overnight. Water and EtOAc were added. The mixture wasfiltered. The organic layer was separated, then purified by silica gelcolumn chromatography with hexane followed by 4-6% EtOAc in hexane togive 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g).

A mixture of 1-(4-iodophenyl)-3-methyl-1H-pyrazole (0.98 g, 3.45 mmol),NBS (0.80 g, 4.49 mmol) and AIBN (0.17 g, 1.03 mmol) in CCl₄ (15 mL) washeated at reflux for 5 hrs. After being cooled to room temperature, itwas filtered. The filtrate was concentrated in vacuo. The residue wasdissolved in DMF (8 mL), NaN₃ (0.400 g, 6.15 mmol) was added. Themixture was stirred at room temperature overnight. H₂O and EtOAc wereadded. The organic phase was separated, dried over Na₂SO₄, concentratedin vacuo. The residue was purified by a silica gel column, eluted withhexane, then with 4-6% EtOAc in hexane to give3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (0.10 g).

A mixture of 3-(azidomethyl)-1-(4-iodophenyl)-1H-pyrazole (100 mg, 0.31mmol) and Ra—Ni (50% aq. slurry, 150 mg) in MeOH (8 mL) was hydrogenatedunder balloon H₂ for 3 hrs. It was filtered through celite. The filtratewas concentrated in vacuo to give(1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg).

To a solution of 5-chloro-thiophene-2-carboxylic acid (51 mg, 0.31mmol), (1-(4-iodophenyl)-1H-pyrazol-3-yl)methanamine (78 mg, 0.26 mmol)and TEA (0.100 mL, 0.72 mmol) in DMF (3 mL), BOP (170 mg, 0.38 mmol) wasadded. The mixture was stirred at room temperature overnight. H₂O andEtOAc were added. The organic phase was separated, washed with 5%NaHCO₃, dried over Na₂SO₄, concentrated in vacuo. The residue waspurified by a preparative TLC plate (developed in EtOAc/hexane (35/65))to give5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide(60 mg).

A mixture of5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide(60 mg, 0.14 mmol), 2-hydroxypyridine (30 mg, 0.32 mmol),8-hydroxyquinoline (10 mg, 0.070 mmol) and K₂CO₃ (50 mg, 0.36 mmol) inDMSO (1 mL) was degassed with Argon before being charged with CuI (15mg, 0.080 mmol). The mixture in a sealed tube was heated at 130° C.overnight. It was then purified by HPLC to give the titled compound (15mg). MS 411.0 and 413.0 (M+H, Cl pattern).

Example 705-Chloro-N-((1-(3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide(115)

The title compound was prepared using a similar procedure as describedin Example 1 for preparing compound 1.6. MS found for C₂₀H₁₆ClN₅O₃S(M+H)+ 442.1, 444.1.

The compounds in the following Table 2 were prepared using methodssimilar to those above or using methods similar to those disclosed inU.S. patent application Ser. No. 11/158,274, filed Jun. 20, 2005, whichclaims the benefit of U.S. Provisional Application No. 60/580,899, filedJun. 18, 2004, which applications are incorporated herein by referencein their entireties.

TABLE 2 Compound Structure Name MS 7

5-Chloro-N-((1-(4-(2- ((dimethylamino)meth- yl)-1H-imidazol-1-yl)-2-fluorophenyl)- 1H-1,2,3-triazol-4- yl)methyl)thiophene-2-carboxamide 460.1 8

5-Chloro-N-((1-(4-(2- methyl-1H-imidazol- 1-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 399.1 10

5-Chloro-N-((1-(4-(2- oxoimidazolidin-1- yl)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene- 2-carboxamide 403.1 15

N-((1-(4-(1H-Indol-2- yl)phenyl)-1H-1,2,3- triazol-4-yl)methyl)-5-chlorothiophene-2- carboxamide 434 16

5-Chloro-N-((1-(4- (methylsulfonyl)phen- yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 397.0 17

5-Chloro-N-((1-(3- fluoro-2′- sulfamoylbiphenyl-4-yl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 492.0 20

N-((1-(4- Carbamoylphenyl)- 1H-1,2,3-triazol-4- yl)methyl)-5-chlorothiophene-2- carboxamide 362.0 22

5-Chloro-N-((1-(4- (methyl(2- (methylamino)ethyl) amino)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 405.1 23

5-Chloro-N-((1-(4- (methylamino)phenyl)- 1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 348.1 29

5-Chloro-N-((1-(4-(2- hydroxyethoxy)phen- yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 379.1 41

N-((1-(4- Aminophenyl)-1H- imidazol-4- yl)methyl)-5- chlorothiophene-2-carboxamide 333.0 42

5-Chloro-N-((1-(4- (2,5-dihydro-1H- pyrrole-1- carbonyl)phenyl)-1H-imidazol-4- yl)methyl)thiophene- 2-carboxamide 413.1 44

N-((1-(4-(2- Oxopyridin-1(2H)- yl)phenyl)-1H- imidazol-4-yl)methyl)acetamide 309.1 47

5-Chloro-N-((2,5- dibromo-1-(4-(N,N- dimethylcarbamimido yl)phenyl)-1H-imidazol-4- yl)methyl)thiophene- 2-carboxamide 544.0, 546.0, 548.0 48

5-Chloro-N-((2,5- dibromo-1-(4- (imino(pyrrolidin-1- yl)methyl)phenyl)-1H-imidazol-4- yl)methyl)thiophene- 2-carboxamide 570.0, 572.0, 574.0 49

5-Chloro-N-((2,5- dibromo-1-(4-(1- methyl-4,5-dihydro- 1H-imidazol-2-yl)phenyl)-1H- imidazol-4- yl)methyl)thiophene- 2-carboxamide 556.0,558.0, 560.0 50

5-Chloro-N-((1-(4-(9- methyl-2,6-dioxo-1H- purin-3(2H,6H,9H)-yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide 483.152

5-Chloro-N-((4- methyl-1-(4-(2- oxopyridin-1(2H)- yl)phenyl)-1H-imidazol-5- yl)methyl)thiophene- 2-carboxamide 425.1 53

5-Chloro-N-((1-(4-(2- oxopyrazin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene- 2-carboxamide 413.1 56

5-Chloro-N-((1-(4-(2- oxotetrahydropyrimidin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 417.1 76

5-Chloro-N-((1-(4-(2- oxo-5-(2-(piperidin-1- yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide539.1 77

5-Chloro-N-((1-(4-(5- (2- morpholinoethoxy)-2- oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide 541.178

5-Chloro-N-((1-(4-(5- nitro-2-oxopyridin- 1(2H)-yl)phenyl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 457 88

5-Chloro-N-((1-(4-(4- (2- (dimethylamino)ethyl)- 2,3-dioxo-3,4-dihydropyrazin- 1(2H)-yl)phenyl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 500.1 89

5-Chloro-N-((1-(4-(3- hydroxy-6- oxopyridazin-1(6H)-yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide 429.190

2-((1-(4-(2- Oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-yl)methylcarbamoyl) benzoic acid 414.1 91

N-((1-(2-(3- Oxopiperazin-1-yl)-4- (2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3- triazol-4- yl)methyl)thiophene- 2-carboxamide 476.192

5-Chloro-N-((1-(4-(1- methyl-4,5-dihydro- 1H-imidazol-2-yl)phenyl)-1H-1,2,3- triazol-5- yl)methyl)thiophene- 2-carboxamide 401.193

5-Chloro-N-((1-(4- (N,N- dimethylcarbamimido yl)phenyl)-1H-1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 389.1 94

5-Chloro-N-((1-(4- (imino(pyrrolidin-1- yl)methyl)phenyl)-1H-1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 415.1 95

5-Chloro-N-((1-(4- (imino(piperidin-1- yl)methyl)phenyl)-1H-1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 429.1 96

N-((1-(4- Carbamoylphenyl)- 1H-1,2,3-triazol-5- yl)methyl)-5-chlorothiophene-2- carboxamide 362.0 97

5-Chloro-N-((1-(4- (methylsulfonyl)phen- yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene- 2-carboxamide 397.0 98

5-Chloro-N-((1-(4-(2- oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-5-yl)methyl)thiophene- 2-carboxamide 412.1 99

5-Chloro-N-((1-(4- (pyridin-2- ylthio)phenyl)-1H- 1,2,3-triazol-5-yl)methyl)thiophene- 2-carboxamide 428.0 100

5-Chloro-N-((1-(6- (pyrrolidin-1- yl)pyridin-3-yl)-1H- 1,2,3-triazol-4-yl)methyl)thiophene- 2-carboxamide 389.1 101

1-(5-(4-((5- Chlorothiophene-2- carboxamido)methyl)- 1H-1,2,3-triazol-1-yl)pyridin-2- yl)piperidine-4- carboxylic acid 447.1 102

N-((1-(6-(Azepan-1- yl)pyridin-3-yl)-1H- 1,2,3-triazol-4- yl)methyl)-5-chlorothiophene-2- carboxamide 417.1 103

5-Chloro-N-((1-(6-(4- methyl-1,4-diazepan- 1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 432.1 104

N-((1-(6-(1,4- Diazepan-1- yl)pyridin-3-yl)-1H- 1,2,3-triazol-5-yl)methyl)-5- chlorothiophene-2- carboxamide 418.1 105

5-Chloro-N-((1-(6-(4- methylpiperazin-1- yl)pyridin-3-yl)-1H-1,2,3-triazol-5- yl)methyl)thiophene- 2-carboxamide 418.1 106

5-Chloro-N-((1-(6- (piperazin-1- yl)pyridin-3-yl)-1H- 1,2,3-triazol-5-yl)methyl)thiophene- 2-carboxamide 404.1 107

5-Chloro-N-(4-(4-((5- chlorothiophene-2- carboxamido)methyl)-1H-imidazol-1- yl)benzyl)thiophene- 2-carboxamide 491.0, 493.0 113

5-Chloro-N-((1-(3-(2- oxopyridin-1(2H)- yl)phenyl)-1H-1,2,3- triazol-4-yl)methyl)thiophene- 2-carboxamide 412.1 114

5-Chloro-N-((1-(4- methyl-3-oxo-3,4- dihydro-2H- benzo[β][1,4]oxazin-7-yl)-1H-1,2,3-triazol- 4- yl)methyl)thiophene- 2-carboxamide 404 116

5-Chloro-N-((1-(5-(2- oxopyridin-1(2H)- yl)quinolin-8-yl)-1H-1,2,3-triazol-4- yl)methyl)thiophene- 2-carboxamide 463

Example 71

This example illustrates methods for evaluating the compounds of theinvention, along with results obtained for such assays. The in vitro andin vivo human Factor Xa activities of the inventive compounds can bedetermined by various procedures known in the art, such as a test fortheir ability to inhibit the activity of human plasma Factor Xa. Thepotent affinities for human Factor Xa inhibition exhibited by theinventive compounds can be measured by an IC₅₀ value (in nM). The IC₅₀value is the concentration (in nM) of the compound required to provide50% inhibition of human Factor Xa proteolytic activity. The smaller theIC₅₀ value, the more active (potent) is a compound for inhibiting FactorXa activity.

An in vitro assay for detecting and measuring inhibition activityagainst Factor Xa is as follows:

IC₅₀ and Ki Determinations: Substrate:

The substrate S-2765 (Z-D-Arg-Gly-Arg-pNA.HCl) was obtained fromDiapharma (West Chester, Ohio).

Enzyme:

The human plasma protein factor Xa was purchased from HaematologicTechnologies (Essex Junction, Vt.).

Methods

IC₅₀ Determinations

All assays, which are performed in 96-well microliter plates, measureproteolytic activity of the enzyme (factor Xa) by following cleavage ofa paranitroanilide peptide substrate. The assay buffer used forproteolytic assays was Tris buffered saline (20 mM Tris, 150 mM NaCl, 5mM CaCl₂, 0.1% Bovine serum albumin (BSA), 5% Dimethyl Sulfoxide (DMSO)pH 7.4). In a 96-well microtiter plate, inhibitor was serially dilutedto give a range of final concentrations from 0.01 nM to 10 μM. Duplicatesets of wells were assayed and control wells without inhibitor wereincluded. Enzyme was added to each well, (factor Xa concentration=1 nM),the plate was shaken for 5 seconds and then incubated for 5 minutes atroom temperature. S-2765 was added (100 μM final) and the plate wasshaken for 5 seconds (final volume in each well was 200 μl). The degreeof substrate hydrolysis was measured at 405 nm on a Thermomax platereader (Molecular Devices, Sunnyvale, Calif.) for 2 minutes. The initialvelocities of substrate cleavage (mOD/min), for each range of inhibitorconcentrations, were fitted to a four parameter equation using Softmaxdata analysis software. The parameter C, derived from the resultingcurve-fit, corresponded to the concentration for half maximal inhibition(IC₅₀).

K_(i) Determination

The assay buffer for this series of assays was Hepes buffered saline (20mM Hepes, 150 mM NaCl, 5 mM CaCl₂, 0.1% PEG-8000, pH 7.4). In a 96-wellmicrotiter plate, inhibitor was serially diluted in a duplicate set ofwells to give a range of final concentrations from 5 μM to 3 μM.Controls without inhibitor (8 wells) were included. The enzyme, factorXa (final concentration=1 nM) was added to the wells. The substrateS-2765 (final concentration=200 μM) was added and the degree ofsubstrate hydrolysis was measured at 405 nm on a Thermomax plate readerfor 5 minutes, using Softmax software. Initial velocities (mOD/min) wereanalyzed by non-linear least squares regression in the Plate K, software(BioKin Ltd, Pullman, Wash.) (Kusmic, et al., Analytical Biochemistry281: 62-67, 2000). The model used for fitting the inhibitordose-response curves was the Morrison equation. An apparent K_(i) (Ki*)was determined. The overall K was calculated using the followingequation:

${Ki} = \frac{{Ki}^{*}}{1 + \frac{\lbrack S\rbrack}{Km}}$

where [S] is substrate concentration (200 μM) and K_(m) is the Michaelisconstant for S-2765.

The following compounds exhibited Factor Xa IC₅₀ values less than orequal to 100 nM: 1, 3, 4, 7-9, 18, 19, 21, 22, 27, 28, 39, 40, 42, 45,47-49, 53, 56, 59, 60, 62-74, 79-83, 86, 87, 98, 115.

The following compounds exhibited Factor Xa IC₅₀ values greater than 100nM and less than 500 nM: 5, 6, 10, 20, 24-26, 37, 46, 61, 78, 100, 102.

The following compounds exhibited Factor Xa IC₅₀ values greater than orequal to 500 nM: 11-17, 23, 29, 38, 41, 43, 44, 50-52, 75-77, 84, 85,88-97, 99, 101, 103-106, 113, 114, 116.

1-19. (canceled)
 20. A method for preventing or treating thrombosis in amammal comprising administering to said mammal a therapeuticallyeffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt, ester, prodrug or composition thereof

wherein: R¹ is selected from the group consisting of halogen, C₁₋₈alkyl, C₂₋₈ alkenyl, and C₂₋₈ alkynyl; R² is hydrogen or C₁₋₄ alkyl; Ais selected from the group consisting of:

 wherein the wavy line indicates the point of attachment to ring B andthe dashed line indicates the point of attachment to the rest of themolecule; R³ is independently hydrogen or R^(3a); R^(3a) isindependently selected from the group consisting of halogen, C₁₋₈ alkyl,C₂₋₈ alkenyl, and C₂₋₈alkynyl; m is 0, 1, 2, or 3; X is C—R⁴ or N or Xand Y are C and are fused to a 6-membered aryl, heteroaryl, orheterocyclic ring; Y is C—R⁵ or N provided that X and Y are not both N;R⁴ is selected from the group consisting of hydrogen, halogen, and

R^(4a) is hydrogen or C₁₋₈ alkyl; R⁵ is selected from the groupconsisting of hydrogen, halogen, and C₁₋₈alkoxy; or R⁵ and R⁶ togetherjoin to form a 6-membered aryl, heteroaryl, or heterocyclic ring fusedto ring B; R⁶ is selected from the group consisting of —R^(6a),—NR^(7a)R^(7b), —NR^(7a)C(O)R^(7c), —NR^(7a)C(O)OR^(7c),—CONR^(8a)R^(8b), —OR^(7c), —SR^(7c), —C(═NR^(7a))NR^(8a)R^(8b),—S(O)₂NR^(8a)R^(8b), and —S(O)₂R^(7c); R^(6a) is selected from the groupconsisting of

 wherein R⁸ can be at any position suitable for a substituent, and if R⁸is attached to a nitrogen atom, then it replaces the hydrogen atomattached thereto; R^(7a) and R^(7b) are independently selected from thegroup consisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substitutedwith one to three R⁹; R^(7c) is selected from the group consisting ofaryl, heteroaryl, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with one tothree R⁹; R⁸ is independently selected from the group consisting ofnitro, hydroxyl, —CO₂H, —C(O)R^(8c), —C(O)NR^(8a)R^(8b), —NR^(8a)R^(8b),—SO₂NR^(8a)R^(8b), halogen, C₁₋₈ alkyl, and C₁₋₈ alkoxy wherein saidC₁₋₈ alkyl and C₁₋₈ alkoxy are optionally substituted with one to threeR⁹; R^(8a) and R^(8b) are independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, and C₁₋₈ alkyl substituted with oneto three R⁹, or R^(8a) and R^(8b) together form a 5 to 7 memberedheterocyclic ring optionally substituted with one to three R⁹ andoptionally having one additional ring heteroatom selected from N, O, orS; R^(8c) is selected from the group consisting of C₁₋₈ alkyl and C₁₋₈alkyl substituted with one to three R⁹; R⁹ is independently selectedfrom the group consisting of halogen, heterocyclic, heteroaryl, —OH,—R¹⁰, —OR¹⁰, —SR¹⁰, —S(O)R¹⁰, —S(O)₂R¹⁰, —SO₂NH₂, —C(O)NH₂, —C(O)R¹⁰,—C(NH)R¹⁰, —NHC(O)R¹⁰, —NHC(NH)R¹⁰, —NHC(O)NH₂, —CO₂H, —NH₂, —NHR¹⁰,—N(R¹⁰)₂ and —N(R¹⁰)₃ ⁺; each R¹⁰ is independently C₁₋₆ alkyl; and n is0, 1, 2, or 3; provided that when X is C—R⁴, Y is C—R⁵, R⁶ is R^(6a),and A is

then R^(6a) is bound to ring B through a carbon atom.
 21. The method ofclaim 20 wherein R¹ is 2-chloro.
 22. The method of claim 20 wherein R²is hydrogen.
 23. The method of claim 20 wherein X and Y are CH.
 24. Themethod of claim 20 wherein A is selected from the group consisting of:


25. The method of claim 20 wherein R⁶ is R^(6a).
 26. The method of claim25 wherein R^(6a) is selected from the group consisting of:


27. The method of claim 20 wherein R⁶ is selected from the groupconsisting of:


28. The method of claim 20 wherein R⁶ is selected from the groupconsisting of:


29. The method of claim 20 wherein R⁶ is selected from the groupconsisting of:


30. The method of claim 20 wherein R⁶ is selected from the groupconsisting of:


31. The method of claim 20 wherein R⁶ is selected from the groupconsisting of:


32. The method of claim 20 wherein R⁶ is

and R⁸ is as previously defined.
 33. The method of claim 32, wherein R⁸is selected from the group consisting of: hydrogen,


34. The method of claim 20 wherein the compound is selected from thegroup consisting of:5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)-2-(piperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-(4-ethylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-(4-isopropylpiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2,4-dimethoxypyrimidin-5-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-2-fluorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxoimidazolidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2′-methoxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(T-hydroxybiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2′-(trifluoromethoxy)biphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(6-chloropyridin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-(1H-Indol-2-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(methylsulfonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(3-fluoro-2′-sulfamoylbiphenyl-4-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(pyrrolidine-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-Carbamoylphenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,N-((1-(4-(2-Amino-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(methyl(2-(methylamino)ethyl)amino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(N-methylpropionamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,Ethyl4-(44(5-chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl(methyl)carbamate,5-Chloro-N-((1-(4-(2-methoxy-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-(dimethylamino)-N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(N-methylacetamido)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-hydroxyethoxy)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((3-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-5-methyl-4,5-dihydroisoxazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((5-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-4,5-dihydro-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((2-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,2-dihydropyridin-3-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((6-oxo-1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1,6-dihydropyridin-3-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-methyl-2-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-methoxypyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-Aminophenyl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(2,5-dihydro-1H-pyrrole-1-carbonyl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,4-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)benzamide,N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)acetamide,5-Chloro-N-((1-(5-(2-oxopyridin-1(2′-1)-yl)pyridin-2-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(6-(2-oxopyridin-1(2H)-yl)pyridin-3-yl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((2,5-dibromo-1-(4-(N,N-dimethylcarbamimidoyl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((2,5-dibromo-1-(4-(imino(pyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((2,5-dibromo-1-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(9-methyl-2,6-dioxo-1H-purin-3(2H,6H,9H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-1H-imidazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((4-methyl-1-(4-(2-oxopyridin-1(211)-yl)phenyl)-1H-imidazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-fluoro-4-(2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxotetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-fluoro-4-(2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-fluoro-4-(3-methyl-2-oxo-tetrahydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(2-fluoro-4-(2-oxopiperidin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(3-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-hydroxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-methoxyethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-(dimethyl(dimethylamino)amino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxo-3-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxo-3-(3-(piperidin-1-yl)propoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-(methylthio)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-(methylsulfinyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-(methylsulfonyl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-(3-(2-(1H-Imidazol-1-yl)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-N-Chloro-N-((1-(4-(3-((1-methyl-1H-imidazol-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(5-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-N-Chloro-N-((1-(4-(5-(2-(dimethylamino)ethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxo-5-(2-(piperidin-1-yl)ethoxy)pyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(5-(2-morpholinoethoxy)-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(5-nitro-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-(4-Amino-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,N-((1-(4-(4-Amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(4-methyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(4-isopropyl-2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,4-(4-(4((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)phenyl)-3-oxopiperazine-1-carboxamide,5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(4-(2-(dimethylamino)ethyl)-2,3-dioxo-3,4-dihydropyrazin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(3-hydroxy-6-oxopyridazin-1(6H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,2-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methylcarbamoyl)benzoicacid,N-((1-(2-(3-oxopiperazin-1-yl)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(N,N-dimethylcarbamimidoyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(imino(pyrrolidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(imino(piperidin-1-yl)methyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,N-((1-(4-Carbamoylphenyl)-1H-1,2,3-triazol-5-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(4-(methylsulfonyl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(pyridin-2-ylthio)phenyl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(6-(pyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,1-(5-(4-((5-Chlorothiophene-2-carboxamido)methyl)-1H-1,2,3-triazol-1-yl)pyridin-2-yl)piperidine-4-carboxylicacid,N-((1-(6-(Azepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,N-((1-(6-(1,4-Diazepan-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)-5-chlorothiophene-2-carboxamide,5-Chloro-N-((1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(6-(piperazin-1-yl)pyridin-3-yl)-1H-1,2,3-triazol-5-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-(4-(4((5-chlorothiophene-2-carboxamido)methyl)-1H-imidazol-1-yl)benzyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrrol-3-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyrazin-1(2H)-yl)phenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-pyrazol-3-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(3-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[β][1,4]oxazin-7-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,5-Chloro-N-((1-(3-methoxy-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,and5-Chloro-N-((1-(5-(2-oxopyridin-1(2H)-yl)quinolin-8-yl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide,or a pharmaceutically acceptable salt, ester, or prodrug thereof. 35.The method of claim 20, wherein the thrombosis is associated with acondition selected from the group consisting of acute coronary syndrome,myocardial infarction, unstable angina, refractory angina, occlusivecoronary thrombus occurring post-thrombolytic therapy or post-coronaryangioplasty, a thrombotically mediated cerebrovascular syndrome, embolicstroke, thrombotic stroke, transient ischemic attacks, venousthrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy,disseminated intravascular coagulation, thrombotic thrombocytopenicpurpura, thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation such as cardiac or other intravascularcatheterization, intra-aortic balloon pump, coronary stent or cardiacvalve, and conditions requiring the fitting of prosthetic devices. 36.The method of claim 35, wherein the condition is selected from the groupconsisting of embolic stroke, thrombotic stroke, venous thrombosis, deepvenous thrombosis, acute coronary syndrome, and myocardial infarction.